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The advent of AlphaFold2 (AF2) has brought AI applications in drug development to unprecedented heights. Its groundbreaking ability to accurately predict protein structures is transformative for identifying new drug targets and designing effective drug molecules. G protein-coupled receptors (GPCRs) are major drug targets, yet their complex and dynamic structures pose significant challenges to traditional structural analysis methods. By using machine learning, AF2 can accurately predict the 3D structures of GPCRs with atomic-level accuracy and remarkable scalability, providing crucial structural insights for drug development. The AlphaFold database encompasses over 200 million proteins, aiding structural biology, protein design, and function prediction. However, the impact on structure-based ligand discovery remained uncertain due to the necessity for accurately modeled binding sites. This study examines these concerns by comparing AF2's predictions with experimental structures for docking experiments. Lyu et al. prospectively docked ultra-large libraries of molecules against unrefined AF2 models of the σ2 and 5-HT2A serotonin receptors, comparing the results to docking against experimental structures. They found that AF2 models achieved accurate side-chain predictions and successfully docked high-affinity ligands. For the σ2 receptor, AF2 predicted side-chain conformations with an RMSD of 1.1 Å from the crystal structure. Docking 490 million molecules against the σ2 receptor's AF2 model yielded a 54% hit rate, comparable to the 51% hit rate using the crystal structure. For the 5-HT2A receptor, AF2 models showed some variations at key residues, and docking 1.6 billion molecules resulted in high hit rates. Of 161 molecules tested, 42 substituted more than 50% of [³H]-LSD at 10 μM, achieving a 26% hit rate. The highest affinity compounds (15 to 24 nM) were identified from AF2 docking. Functional activity of selected compounds was assessed across 5-HT2A, 5-HT2B, and 5-HT2C receptors, with several compounds demonstrating subtype selectivity and high potency, some with sub-nanomolar EC50 values, indicating strong and selective receptor binding. This validates AF2's potential in enhancing drug discovery precision and efficiency. Despite its transformative potential, AI in drug development faces several challenges. One significant concern is the reliance on data quality and quantity, where inaccuracies or biases in training data can lead to flawed predictions. Moreover, advanced AI models like AlphaFold3, which can predict complex protein-molecule interactions and post-translational modifications, are now accessible only via a restricted server, unlike its predecessor AlphaFold2. This proprietary nature limits direct access to the model and imposes a cap on daily predictions. The lack of transparency surrounding its operations and usage constraints restricts extensive academic scrutiny. Addressing these challenges is crucial to fully harness AI's potential in accelerating drug discovery and optimizing therapeutic outcomes. Looking ahead, AI offers significant advantages in drug development, such as the ability to tackle complex targets and accurately predict protein-molecule interactions. To fully harness these benefits, it is essential to keep updating and refining the databases with high-quality data. This effort will help resolve issues related to data accuracy and bias, leading to more dependable predictions. Additionally, transparency in AI models and their operations is crucial for building trust and allowing for academic review. Furthermore, AI's role in structural biology and drug design is set to spark innovation in automated screening and large-scale data analysis, paving the way for a new era in precision medicine and medical research. References: Lyu, J. et al. AlphaFold2 structures guide prospective ligand discovery. Science https://doi.org/10.1126/science.adn6354 (2024) Abramson, J., Adler, J., Dunger, J. et al. Accurate structure prediction of biomolecular interactions with AlphaFold 3. Nature 630, 493–500 (2024). https://doi.org/10.1038/s41586-024-07487-w

Hi everyone, Take a moment to explore our latest coverage of GPCRs this week, which includes 7 insightful research papers and industry updates. Stay informed with the most recent developments in GPCR research and industry news. This week's highlight includes congrats to: Dr. John Teye Azietaku for his contributor article on Unveiling GPCR Priming: The Hidden Synergy in Cellular Signalling Alberto Gonzalez-Hernandez, Hermany Munguba, Joshua Levitz for their work on Emerging modes of regulation of neuromodulatory G protein-coupled receptors Dr. GPCR University We are thrilled to announce that Dr. Terry Kenakin will conduct two consecutive courses in September and October 2024. Stay tuned for more details, and mark your calendars for registration opening in July 2024. Dr. GPCR Podcast Tune into the 156th episode of the Dr. GPCR Podcast, featuring Dr. Justin English on "Empowering Drug Discovery for the GPCR Community"! Experience the full impact of our discussions with our new video format. Witness the passion and excitement of our guests as you catch up on missed episodes. GPCR Event Highlight We’re excited to announce our in-person event in collaboration with the Adhesion GPCR Consortium: The 11th Adhesion GPCR Workshop. Join us in vibrant Mexico City from October 23 to 25, 2024, for this key event in adhesion GPCR Biology. Present Your Research: Submit your abstract by June 24th for priority consideration or by July 22nd for the second round. Logo Contest: Showcase your creativity by designing the event logo! Submit your entries by August 15th, 2024. Sponsorship Opportunities: We’re offering sponsorship opportunities for this prestigious event. For more details, contact us at Hello@DrGPCR.com. Let’s dive into the Classified GPCR News from June 10th to 16th, 2024. GPCR Activation and Signaling Emerging modes of regulation of neuromodulatory G protein-coupled receptors GPCRs in Cardiology, Endocrinology, and Taste Chamber-specific contractile responses of atrial and ventricular hiPSC-cardiomyocytes to GPCR and ion channel targeting compounds: A microphysiological system for cardiac drug development GPCRs in Neuroscience Astrocytic PAR1 and mGluR2/3 control synaptic glutamate time course at hippocampal CA1 synapses Regulator of G protein signaling 6 (RGS6) in dopamine neurons promotes EtOH seeking, behavioral reward, and susceptibility to relapse Alcohol consumption does not impact delta and kappa opioid receptor-mediated synaptic depression in dorsolateral striatum of adult male mice Methods & Updates in GPCR Research RNA therapeutics in targeting G protein-coupled receptors: Recent advances and challenges Structural and Molecular Insights into GPCR Function Structural perspectives on chemokine receptors Industry News Exscientia Appoints New Leaders to Strengthen the Impact of Integrated Technologies and Focus Clinical Development Expertise in Oncology Octant Bio will be at the Goldman Sachs Global Healthcare Conference Crinetics Pharmaceuticals gets grant for patent granted for oral method to suppress hormones GPCR Events, Meetings, and Webinars June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein Mediated Signaling Networks June 25 - 29, 2024 | FENS Forum 2024 October 2024 | Biologics US 2024 October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs HIGHLIGHT Principal Scientist, In vitro pharmacology Senior Scientist - Receptor Pharmacology Postdoctoral Scientist Senior Research Associate/Associate Scientist, Protein Science Post-Doctoral Fellow—Pharmacology/Cell Biology/Biochemistry Post Doctoral Fellow Postdoc Position Join Dr. GPCR Ecosystem

G protein-coupled receptors (GPCRs) are a vast family of membrane-bound proteins crucial for transmitting external stimuli into intracellular signals, thereby influencing numerous physiological processes. These receptors typically engage specific G protein subtypes, such as Gs, Gi/o, Gq/11, and G12/13, at the initial GPCR-G protein association step, ensuring precise downstream signalling activation. Traditionally, it was believed that GPCRs selectively activate only their cognate G protein subtypes, avoiding interactions with non-cognate G proteins [1]. However, recent studies have unveiled a complex layer of GPCR functioning, introducing the concept of 'unproductive coupling'[1] and a fascinating phenomenon known as GPCR priming [2]. The concept of unproductive coupling was highlighted by Okashah et al. in 2020 [1]. Using BRET based approaches, the Gs-coupled vasopressin V2 receptor (V2R) was shown to form a stable complex with the non-cognate G12 protein in response to arginine vasopressin. Surprisingly, this interaction did not result in G12 activation, even in the presence of GTP, which is typically necessary for G protein activation. Instead, G12 overexpression inhibited V2R downstream signalling, including β-arrestin recruitment and receptor internalization. This unproductive coupling revealed that non-cognate G protein interactions could modulate GPCR signalling pathways without initiating traditional activation sequences. In 2017, Gupte et al. introduced GPCR priming, which posits that non-cognate G proteins can enhance the coupling efficiency of cognate G proteins to GPCRs, thereby amplifying canonical downstream signalling [2]. This priming effect occurs through non-functional interactions between non-cognate G proteins and GPCRs, facilitating subsequent coupling of cognate G proteins and promoting enhanced signalling. Gupte et al. utilized a systematic protein affinity strength modulation (SPASM) technique to show that Gq proteins could bolster Gs dependent-β2-adrenergic receptor-mediated cAMP signalling, while Gs proteins similarly enhanced Gq dependent-vasopressin receptor-mediated IP1 accumulation. The enhanced signalling observed in GPCR priming is attributed to the formation of temporal non-cognate-GPCR conformational states, which enable more efficient interactions between the GPCR and the cognate Gα C terminus [2, 3]. This suggests that the non-cognate G proteins, although not activating downstream pathways directly, prepare the GPCR in a manner that optimizes subsequent cognate G protein activation. Using CRISPR-Cas9 knockout HEK cells lacking Gs proteins, a study by Stallaert et al. in 2017 showed that Gs played a pivotal role in calcium signalling at the β2-adrenergic receptors (β2AR) [4]. Overall, the increased calcium signalling was attributed to the release of ATP via β2AR-Gs mediated activation, which subsequently transactivates purinergic receptors through Gq in intracellular stores [4]. Thus, this finding raises the possibility that GPCR priming might result not only from intricate receptor-G protein interactions but also from the influence of downstream effector mechanisms. However, IP1 signalling through the non-cognate Gq was not important for the increased β2AR-Gs-mediated cAMP levels in response to isoproterenol. [2]. GPCR priming opens new avenues for understanding the nuanced regulatory mechanisms governing GPCR signalling. It challenges the traditional view of strict cognate G protein coupling and suggests a more dynamic interaction landscape where non-cognate G proteins play a critical preparatory role. This has significant implications for drug development, as targeting these non-cognate interactions could lead to novel therapeutic strategies for modulating GPCR activity. In conclusion, GPCR priming represents a compelling area of research that promises to deepen our understanding of cellular signalling networks. Continued exploration into the molecular mechanisms underlying this phenomenon could unveil new dimensions of GPCR functionality and offer innovative approaches to treating a wide range of diseases. References 1.      Okashah, N., et al., Agonist-induced formation of unproductive receptor-G(12) complexes. Proc Natl Acad Sci U S A, 2020. 117(35): p. 21723-21730. 2.      Gupte, T.M., et al., Priming GPCR signaling through the synergistic effect of two G proteins. Proceedings of the National Academy of Sciences, 2017. 114(14): p. 3756-3761. 3.      Hilger, D., et al., Structural insights into differences in G protein activation by family A and family B GPCRs. Science, 2020. 369(6503). 4.      Stallaert, W., et al., Purinergic Receptor Transactivation by the β(2)-Adrenergic Receptor Increases Intracellular Ca(2+) in Nonexcitable Cells. Mol Pharmacol, 2017. 91(5): p. 533-544.

Hi everyone, Please take a moment to explore our most recent coverage of GPCRs this week, which includes 15 insightful research papers and industry updates. Stay informed with the most recent developments in GPCR research and industry news. This week's highlight includes congrats to: Dr. Monserrat Avila-Zozaya for her contributor article on Navigating the Signaling Network: RTK and GPCR Crosstalk Uncovered Drs. Jürgen Wess and Liu Liu for their study on A novel function of the M2 muscarinic receptor Drs. Zhan-Guo Gao, Mansour Haddad, and Kenneth A Jacobson for their work on A2B adenosine receptor signaling and regulation Dr. GPCR University We are excited to announce that Dr. Terry Kenakin will return for two consecutive courses in September and October 2024. More details will be shared soon, and registration will open in July 2024. Dr. GPCR Podcast The 155th episode of the Dr. GPCR Podcast features a recap of the Endocrine Metabolic GPCRs 2024 with the organizers, Drs. Aylin Hanyaloglu, Caroline Gorvin, and Alejandra Tomas. It is now available for viewing in video format on our website. Catch up on missed episodes and immerse yourself in the visual experience! GPCR Event Highlight We are thrilled to share the news of our in-person event in partnership with the Adhesion GPCR Consortium: The 11th Adhesion GPCR Workshop. This significant event in adhesion GPCR Biology will be held in vibrant Mexico City from October 23 to 25, 2024. Join the global GPCR community to present your research—submit your abstract using this form. Deadline 1st round priority: June 24th / 2nd round: July 22th Do you have an artistic side? If so, participate in our logo contest for the event! Submit your logo and review the rules. The contest deadline is August 15th, 2024. We are also offering sponsorship opportunities for this exciting event, which brings together scientists worldwide to explore all aspects of adhesion GPCR biology. Interested in sponsoring? Please email us at Hello@DrGPCR.com. Let’s dive into the Classified GPCR News from June 3rd to June 9th, 2024. Adhesion GPCRs A correlation study of adhesion G protein-coupled receptors as potential therapeutic targets for breast cancer GPCR Activation and Signaling The TAS1R2 G-protein-coupled receptor is an ambient glucose sensor in skeletal muscle that regulates NAD homeostasis and mitochondrial capacity Differential activation of rhodopsin triggers distinct endocytic trafficking and recycling in vivo via differential phosphorylation Increased transcriptional elongation and RNA stability of GPCR ligand binding genes unveiled via RNA polymerase II degradation Growth factor-dependent phosphorylation of Gαi shapes canonical signaling by G protein-coupled receptors Kinetic Model for the Desensitization of G Protein-Coupled Receptor RNA-seq screening and gene function analysis uncover GPR183 as a key mediator for methionine to stimulate milk synthesis in mouse mammary epithelial cells GPCR Binders, Drugs, and more Structure-based identification of a G protein-biased allosteric modulator of cannabinoid receptor CB1 GPCR function in autophagy control: a systematic approach of chemical intervention Methods & Updates in GPCR Research ORP9-PH domain-based fluorescent reporters for visualizing phosphatidylinositol 4-phosphate dynamics in living cells Reviews, GPCRs, and more Restoring function to inactivating G protein-coupled receptor variants in the hypothalamic-pituitary-gonadal axis1 A novel function of the M2 muscarinic receptor A2B adenosine receptor signaling and regulation Novel medications for problematic alcohol use Structural and Molecular Insights into GPCR Function Structural basis for recognition of 26RFa by the pyroglutamylated RFamide peptide receptor Industry News NanoImaging Services and Cube Biotech Collaborate to Enhance Cryo-EM Enabled Gene to Structure Workflow Domain Therapeutics Strengthens Its Intellectual Property for Its Series of Treg Depleting anti-CCR8 Antibodies, Including Best-in-class Candidate DT-7012 Crinetics Announces Positive Initial Findings at ENDO 2024 for Atumelnant in Two Ongoing, Open-Label Studies for the Treatment of Congenital Adrenal Hyperplasia (CAH) and ACTH-Dependent Cushing’s Syndrome (ADCS) Septerna Presents Preclinical Data at ENDO 2024 Highlighting Therapeutic Potential of its GPCR Drug Discovery Platform GPCRs and Emotional Pain: Exploring Non-Narcotic Pathways to Relief GPCR Events, Meetings, and Webinars June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein Mediated Signaling Networks June 25 - 29, 2024 | FENS Forum 2024 October 2024 | Biologics US 2024 October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs HIGHLIGHT Principal Scientist, In vitro pharmacology Senior Scientist - Receptor Pharmacology Postdoctoral Scientist Senior Research Associate/Associate Scientist, Protein Science Post-Doctoral Fellow—Pharmacology/Cell Biology/Biochemistry Post Doctoral Fellow Postdoc Position Join Dr. GPCR Ecosystem

One fascinating aspect of the cellular signaling network is the crosstalk between G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). GPCRs, known for their involvement in a myriad of physiological processes, mediate mostly signaling through heterotrimeric G proteins. On the other hand, RTKs play pivotal roles in growth factor signaling, regulating cell growth, differentiation, and survival. The interaction between these two receptor types raises intriguing questions about how their signaling pathways intersect and influence each other to orchestrate cellular responses. The cross-talk between growth factor receptors and GPCRs is an intriguing area of study. Recently, Suchismita Roy et al. have explored how growth factors can modulate canonical G protein signaling, shedding light on molecular mechanisms with significant implications for both physiology and pathology. The primary research question addressed in this study was: How do growth factors, specifically through RTKs, modulate canonical heterotrimeric G protein signaling? The researchers focused on the phosphorylation of the G protein subunit Gαi at specific residues within three strategic hotspots: the P loop, the interdomain cleft, and the C terminus. They employed a series of phospho-mimicking mutants and assays such as linear ion trap mass spectrometry, BRET, pull down, and transwell cell migration assays to investigate the effects of these modifications on key signaling events such as receptor recruitment, trimer dissociation, cAMP inhibition, and chemotaxis. The study revealed that the epidermal growth factor-induced phosphorylation of Gαi at specific residues predominantly inhibits ligand-induced signaling while promoting constitutive Gβγ signaling. Key findings include: Phosphorylation Hotspots: P Loop (Ser44, Ser47, Thr48): Impairs ligand-stimulated Gβγ release and cAMP suppression, potentially acting as dominant-negative proteins. Interdomain Cleft (Ser151, Tyr154, Tyr155): Phosphorylation at Tyr154 and Tyr155 impaired ligand-stimulated Gβγ release, cAMP suppression, and chemotaxis while enhancing constitutive Gβγ signaling. Computational analyses indicated that these modifications favor the nucleotide-free state of Gαi. C Terminus (Tyr320): Phosphorylation at Tyr320 disrupted Gβγ binding, receptor coupling, and ligand-stimulated signaling, resulting in impaired chemotaxis. Notably, the Y320F mutation restored some signaling capabilities, emphasizing Tyr320's role in membrane localization and signaling efficiency. Mechanisms of Inhibition: The study identified three distinct mechanisms by which phosphorylation inhibits canonical signaling, based on the location of the phosphosites within the G protein. Signaling Pathway Segregation: Phosphorylation events in the interdomain cleft and P loop uncouple G proteins from GPCRs, leading to segregation of RTK-to-Gαi pathways from canonical GPCR-to-Gαi pathways. These findings have broad implications for understanding cellular signaling in both normal physiology and pathological conditions. The ability of growth factors to modulate G protein signaling through specific phosphorylation events highlights a nuanced regulatory mechanism that could be crucial in contexts such as cancer progression and wound healing. For instance, the sequestration of G proteins from canonical GPCR-dependent pathways by growth factor signaling might contribute to altered cellular behaviors in cancer, promoting uncontrolled cell migration and invasion. Moreover, the study's insights into the structural and functional consequences of specific phosphorylation events provide a deeper understanding of the molecular basis for cross-talk between RTKs and GPCRs. This knowledge could inform the development of therapeutic strategies aimed at targeting specific phosphorylation events to modulate G protein signaling in disease. In conclusion, this research elucidates the molecular mechanisms by which growth factors influence G protein signaling, revealing the strategic importance of phosphorylation at specific residues. These findings enhance our understanding of cellular signaling dynamics and open new avenues for therapeutic intervention in diseases characterized by dysregulated signaling pathways. Reference Roy, S., Sinha, S., Silas, A. J., Ghassemian, M., Kufareva, I., & Ghosh, P. (2024). Growth factor-dependent phosphorylation of Gαi shapes canonical signaling by G protein-coupled receptors. Science signaling, 17(839), eade8041. https://doi.org/10.1126/scisignal.ade8041

Hello everyone! Take a moment to browse our latest coverage of GPCRs this week, featuring 24 insightful research papers and industry updates. Stay informed with the most recent developments in GPCR research and industry news. This week's highlight includes congrats to: Inês Pinheiro, for her Dr. GPCR contributor article Canonical chemokine receptors as scavenging “decoys” Shivani Sachdev, Brendan Creemer, Thomas Gardella, and Ross Cheloha for their work on Highly biased agonism for GPCR ligands via nanobody tethering Elk Kossatz, Michel Bouvier, Jana Selent, et al. for their study on G protein-specific mechanisms in the serotonin 5-HT2A receptor regulate psychosis-related effects and memory deficits Dr. GPCR University We are excited to announce that Dr. Terry Kenakin will return for two consecutive courses in September and October 2024. More details will be shared soon, and registration will open in July 2024. Dr. GPCR Podcast Episode 154 of the Dr. GPCR Podcast on Self-Learning, Collaboration, and Delegation in Science with Dr. Badr Sokrat is live! You can now watch podcast episodes in video format on our website. Catch up on missed episodes and enjoy the visual experience! GPCR Event Highlight We are excited to announce our first in-person event in collaboration with the Adhesion GPCR Consortium: The 11th Adhesion GPCR Workshop will take place in vibrant Mexico City from October 23 to 25, 2024. Join the global GPCR community to share your research—submit your abstract using this form. We are also offering sponsorship opportunities for this exciting event, which unites scientists worldwide to explore all aspects of adhesion GPCR biology. Interested in sponsoring? Please email us at Hello@DrGPCR.com. Let’s dive into the Classified GPCR News from May 27th to June 2nd, 2024. GPCR Activation and Signaling Highly biased agonism for GPCR ligands via nanobody tethering Mechanistic insights into G-protein activation via phosphorylation mediated non-canonical pathway GPCR Screening Reveals that the Metabolite Receptor HCAR3 Regulates Epithelial Proliferation, Migration, and Cellular Respiration G protein-specific mechanisms in the serotonin 5-HT2A receptor regulate psychosis-related effects and memory deficits GPCRs in Cardiology, Endocrinology, and Taste The full-length TSH receptor is stabilized by TSH ligand Cardiomyocyte-specific overexpression of GPR22 ameliorates cardiac injury in mice with acute myocardial infarction GPCRs in Neuroscience Voltage tunes mGlu5 receptor function, impacting synaptic transmission Orphan receptor GPR88 as a potential therapeutic target for CNS disorders - an in silico approach GRN knockdown regulates the expression and alternative splicing of genes associated with aphasia-related diseases in PC12 cells 17-β-estradiol potentiates the neurotrophic and neuroprotective effects mediated by the dopamine D3/acetylcholine nicotinic receptor heteromer in dopaminergic neurons A new GRAB sensor reveals differences in the dynamics and molecular regulation between neuropeptide and neurotransmitter release GPCRs in Oncology and Immunology Neurotoxicity and accumulation of CPPD quinone at environmentally relevant concentrations in Caenorhabditis elegans Comparison of infectious complications with BCMA-directed therapies in multiple myeloma Glucose and HODEs regulate Aspergillus ochraceus quorum sensing through the GprC-AcyA pathway Deciphering the genetic landscape of lumpy skin disease: Unraveling variable virulence through comprehensive genome sequence analysis in India Methods & Updates in GPCR Research Engineering G protein-coupled receptors for stabilization Cryo-electron microscopy for GPCR research and drug discovery in endocrinology and metabolism Chemogenetic Signaling in Space and Time: Considerations for Designing Neuroscience Experiments Using DREADDs Reviews, GPCRs, and more ERNEST COST action overview on the (patho)physiology of GPCRs and orphan GPCRs in the nervous system Why classical receptor theory, which ignores allostery, can effectively measure the strength of an allosteric effect as agonist's efficacy Single transmembrane GPCR modulating proteins: neither single nor simple Structural and Molecular Insights into GPCR Function Insights on the G protein-coupled receptor helix 8 solution structure and orientation using a neurotensin receptor 1 peptide Illuminating the neuropeptide Y4 receptor and its ligand pancreatic polypeptide from a structural, functional, and therapeutic perspective Structural basis for selectivity and antagonism in extracellular GPCR-nanobodies Industry News Structure Therapeutics Reports Positive Topline Data from its Phase 2a Obesity Study and Capsule to Tablet PK Study for its Oral Non-Peptide Small Molecule GLP-1 Receptor Agonist GSBR-1290 Crinetics Pharmaceuticals Appoints Robert M. Cuddihy, M.D., as Senior Vice President of Medical Affairs Septerna to Participate in the Jefferies Global Healthcare Conference Crinetics Announces Positive Initial Findings At Endo 2024 For Atumelnant In Two Ongoing, Open-Label Studies For The Treatment Of Congenital Adrenal Hyperplasia (CAH) And Acth-Dependent Cushing’s Syndrome (ADCS) Nxera Pharma to Receive $4.6 Million in Milestone Payments from Centessa Pharmaceuticals CB1 receptor inverse agonist improves lung functioning in preclinical asthma GPCR Events, Meetings, and Webinars June 2 - 7, 2024 | Chemotactic Cytokines June 4, 2024 | Live Webinar ‘It All Starts With a Protein – Protein Sciences as a Key to Success in Drug Discovery’ June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein Mediated Signaling Networks June 25 - 29, 2024 | FENS Forum 2024 October 2024 | Biologics US 2024 October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs HIGHLIGHT Principal Scientist, In vitro pharmacology Senior Scientist - Receptor Pharmacology PostDoctoral Scientist Senior Research Associate/Associate Scientist, Protein Science Post-Doctoral Fellow—Pharmacology/Cell Biology/Biochemistry Post Doctoral Fellow Postdoc Position Join Dr. GPCR Ecosystem

The immune system depends on chemokines to direct cell migration during immune surveillance and inflammation, as well as to play vital roles in the development, maturation, and homing of lymphocytes and the development of organs. However, an imbalance in the chemokine system can also contribute to various diseases, such as inflammatory conditions and cancer. In all these situations, chemokines interact with seven-transmembrane chemokine-type G protein-coupled receptors (chemokine receptors, CKRs) and glycosaminoglycans (GAGs) to regulate the movement of leukocytes throughout the body, ensuring a functional immune system and an effective response to inflammatory stimuli (Proudfoot, A. E, 2002). In humans there are approximately 45 chemokines, 19 chemotactic or G-protein coupled chemokine receptors (CKRs) that signal via Gαi and 4 official atypical chemokine receptors (ACKRs) which engage in ligand scavenging and favor β-arrestin biased signaling (Murphy, PM. et al. 2000). Indeed, ACKRs behave as scavenging “decoys” in order to either limit chemokines spatial availability or to remove them from in vivo sites, while maintaining the responsiveness of canonical G protein-coupled CKRs that bind to the same ligand(s) (Nibbs, R. J.; Graham, G. J., 2013). Although less characterized, canonical CKRs have also been shown to not only directly regulate migration but also play a scavenging role (e.g. CCR2, CXCR2, CXCR3, and CX3CR1) (Cardona, A. E., et al. 2008). CCR2 is an example of a dual-function receptor that directly regulates both cell migration and scavenging (Volpe S. et al., 2012), which molecular signature was recently characterized (Shroka, T. M, et al. 2023). This study revealed that CCR2 scavenging is independent of G proteins, GRKs, arrestins, as well as clathrin, which is a different mechanism from what has been established for other chemokine scavenger receptors that where shown to couple to GRKs, β-arrestins, or both such as CCR1. CCR1 is constitutively phosphorylated, constitutively interacts with β-arrestin2, and constitutively internalizes in a β-arrestin2-dependent manner (Gillilan, C. T., et al., 2013). Scavenging allows cells to continuously migrate by remaining responsive to chemokines, it dampens the inflammatory response when needed; and it may interfere with other chemokine receptors which share the ligands and ultimately affect cell migration  (Cardona, A. E., et al. 2008). Interestingly, in monocytes and dendritic cells exposed to treatments mimicking inflammation, CCR1, CCR2, and CCR5 switch purely to scavenging (D'Amico G. et al. 2000), becoming incapable of promoting cell migration, a phenomenon which is likely to be mediated by changes in the cell motility machinery with receptor-specific switches. The scavenging function of CKRs should be considered when evaluating the safety and therapeutic efficacy of blocking receptor-ligand binding. For instance, CCR2 inhibition leads to inhibition of scavenging and elevated plasma levels of CCL2 (Aiello, R. J., et al. 2010), which may ultimately compete with receptor antagonists, thereby decreasing the efficacy. To comprehensively elucidate the role of scavenging in normal physiology and the potential implications of its inhibition, an in-depth understanding of the underlying regulatory mechanisms is needed. Enhancing our knowledge of these regulatory frameworks will provide critical insights into the contribution of scavenging to homeostatic maintenance and the pathological consequences that may arise from its disruption.

Hello everyone! Check out our latest coverage of GPCRs this week, featuring 15 insightful research papers and industry updates. Stay informed with the latest GPCR research and industry news. This week's highlight includes congrats to: Cam Sinh Lu, for his first Dr. GPCR contributor article Extracellular signal-regulated kinases – a potential pathway for GPCR-targeted drug discovery Nicola J Smith, Lauren T May, and Natasha L Grimsey for their work on Highlights and hot topics in GPCR research from 'Down Under' Dr. GPCR University Today marks the final day of the Dr. GPCR University workshop on Advanced Data Analysis for GPCR Pharmacology, led by the esteemed Dr. Sam Hoare. It's been a remarkable experience with participants joining us from around the globe. We're thrilled to announce that Dr. Terry Kenakin will return for two consecutive courses in September and October 2024. Stay tuned for more details, and be ready to register in July 2024. Dr. GPCR Podcast We have thrilling news—Episode 153 of the Dr. GPCR Podcast featuring Dr. Jacek Mokrosiński is live! Titled "Embracing Networking for Professional Growth" Our podcast episodes are now available in video format on our website. Revisit your favorite episodes and catch up on any you’ve missed. Tune in and enjoy the visual experience! Dr. GPCR Matchmaking Read Mark's job spotlight article for a Principal Scientist in In Vitro Pharmacology! Mark recently discussed this exciting opportunity with Beth Fleck, Director of In Vitro Pharmacology at Crinetics Pharmaceuticals! GPCR Event Highlight We are delighted to announce our first in-person event in collaboration with the Adhesion GPCR Consortium: The 11th Adhesion GPCR Workshop will be held in vibrant Mexico City from October 23 to 25, 2024. Join the global GPCR community and share your research—submit your abstract using this form. We are also seeking sponsors to support this exciting event that unites scientists worldwide to explore all aspects of adhesion GPCR biology. Interested in sponsoring? Please email us at Hello@DrGPCR.com. Let’s dive into the Classified GPCR News from May 20th to 26th, 2024. Adhesion GPCRs Adhesion G Protein-Coupled Receptor Gpr126 (Adgrg6) Expression Profiling in Diseased Mouse, Rat, and Human Kidneys GPCR Activation and Signaling Differential regulation of G protein-coupled receptor-associated proteins in the caudate and the putamen of cynomolgus macaques following chronic ethanol drinking GRK5 is required for adipocyte differentiation through ERK activation GPCR Binders, Drugs, and more Flipping the GPCR Switch: Structure-Based Development of Selective Cannabinoid Receptor 2 Inverse Agonists Development of Putative Bivalent Dicovalent Ligands for the Adenosine A1 Receptor GPCRs in Cardiology, Endocrinology, and Taste Sodium/Potassium ATPase Alpha 1 Subunit Fine-tunes Platelet GPCR Signaling Function and is Essential for Thrombosis GPCRs in Oncology and Immunology Enterococcus-derived tyramine hijacks α2A-adrenergic receptor in intestinal stem cells to exacerbate colitis The EBI2 receptor is coexpressed with CCR5 in CD4+ T cells and boosts HIV-1 R5 replication Methods & Updates in GPCR Research Evaluation and comparison of colorimetric outputs for yeast-based biosensors in laboratory and point-of-use settings Quantitative proteomics reveals CLR interactome in primary human cells Exploiting Cell-Based Assays to Accelerate Drug Development for G Protein-Coupled Receptors TOR signaling regulates GPCR levels on the plasma membrane and suppresses the Saccharomyces cerevisiae mating pathway Reviews, GPCRs, and more Highlights and hot topics in GPCR research from 'Down Under' Apelin receptor dimer: Classification, future prospects, and pathophysiological perspectives Structural and Molecular Insights into GPCR Function Bilayer lipids modulate ligand binding to atypical chemokine receptor 3 Industry News New cannabinoid CB1 receptor antagonists disclosed in Inversago patent Orion Biotechnology will be attending BIO 2024 Antiverse is attending BIO 2024 Septerna to Present Preclinical Data from GPCR Drug Discovery Engine at ENDO 2024 The Promise of Oxytocin: Novel Approaches for Targeting Oxytocin Receptors in Autism Spectrum Disorder and Psychiatric Disorders GPCR Events, Meetings, and Webinars NEW June 1 - 4, 2024 | ENDO 2024 NEW June 3 - 6, 2024 | BIO 2024 June 2 - 7, 2024 | Chemotactic Cytokines June 4, 2024 | Live Webinar ‘It All Starts With a Protein – Protein Sciences as a Key to Success in Drug Discovery’ June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein Mediated Signaling Networks June 25 - 29, 2024 | FENS Forum 2024 October 2024 | Biologics US 2024 October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs HIGHLIGHT Principal Scientist, In vitro pharmacology NEW Senior Scientist - Receptor Pharmacology NEW PostDoctoral Scientist Senior Research Associate/Associate Scientist, Protein Science Post-Doctoral Fellow—Pharmacology/Cell Biology/Biochemistry Post Doctoral Fellow Postdoc Position Senior Associate Scientist - Global Research Technologies Novo Nordisk Scientist I - Global Research Technologies Novo Nordisk Join Dr. GPCR Ecosystem

Welcome to the 4th official Adhesion GPCR Consortium newsletter! We welcome suggestions, feedback, and announcements from the community. Announcements Please save the date for the 2024 aGPCR workshop hosted by Antony Boucard! This exciting conference will take place from October 23-25th. We'll see you in Mexico City! Please see this website for details on the conference and the Logo Contest! Member Profile Antony Boucard Professor Centro de Investigación y de Estudios Avanzados del IPN (Cinvestav) How did you become involved in adhesion GPCR research? What is your backstory? AB: I became aware of the existence of adhesion GPCRs while completing my graduate studies. The family of adhesion GPCRs called the Latrophilins or ADGRLs first captured my attention due to their involvement in neuronal synapses uncovered through the mechanism of action of a paralyzing component from black spider venom. For my postdoctoral training, I joined one of the labs that participated in Latrophilins’ discovery, the lab of Dr. Thomas Südhof, but did not start working on them right away. This was because, at that time, the neurexins, another family of adhesion molecules that also happened to be targeted by the same spider toxin as latrophilins, were a more pressing matter. Transitioning to study Latrophilins, I decided to test the interaction of neurexins with Latrophilins. To my surprise and delight, the neurexins happened to be ligands for one isoform of the Latrophilins. Another chapter was being written for me and has been in full redaction since then. What do you think is the next great hurdle in the aGPCR field? What challenges will researchers overcome in the next 10 years? AB: One of the big challenges that the field will have to face in the next 10 years is deciphering the physiological relevance of splice-dependent aGPCR diversity. Alternative splicing events account for hundreds, if not thousands, of potentially divergent isoforms throughout many species. The distribution, functionality, and structure of the multiple splice isoforms that adhesion GPCRs possess are currently unknown. This will greatly impact not only the way we understand how aGPCR works but might also provide a guide to how pharmacological approaches will be developed, i.e., splice isoform-specific agonist/antagonist compounds. How did you become involved with the AGC? Who volunteered you to host the next workshop? AB: I became involved with the AGC through a suggestion from one of my colleagues to join this select group, which was getting together to talk about my favorite molecules. If I wanted to be part of the narrative, I felt that I had to join the community. And so I did. My first meeting was in Boston. I still remember entering the Hall at Boston ́s Children Hospital, going to register and being asked who was my PI. As much as I was shocked that I wasn’t asked if I was a student or a PI, I was more proud to say that I was coming as the founder of my own lab. I was volunteered to host the AGC Workshop by two Board members, Tobias Langenhan and Jörg Hamann. I said yes as soon as they approached me. I, in turn, recruited Yamina Berchiche, founder of DrGPCR.com, to join me in this endeavor. What are you most excited about for the upcoming workshop? If someone is flying in from the other side of the globe, what are three things they must experience in Mexico City? AB: The next workshop will likely bring together some of the hottest adhesion GPCR research going on right now and set the tone for the upcoming years. The excitement I felt when I first attended back in Boston is the same one I feel now that I am the organizer. Also, seeing the expanding diversity among the aGPCR community, added to the fact that this will all take place for the first time in a developing country like Mexico, is paramount. There are a lot of firsts in this perspective: the first time in a LATAM country, the first organized by Afro-descendants (Yamina Berchiche, my co-organizer, has African roots, and my origins are Afro-Carribean). This might not be a big deal for many, but in this new era of making sure that historically excluded demographics are finally included, this represents a building block to reinforce the need for diversity in science. A small step toward leveling the playing field. When in Mexico City from 23-25 October, here is my bucket list of the 3 things that people should absolutely experience: The Day of the Dead celebrations: This happens over the weekend during the end of October and takes the shape of costume parades in which everybody contributes their own versions of the Catarinas (Folklore Mexican ghost lady) or explores the mysterious world of the Alebrijes. Of course, there is the famous parade popularized by the James Bond movie Spectre. The food: While in Mexico, eat like one. The diversity is humongous. No wonder why Mexican cuisine has obtained the coveted status of UNESCO ́s Intangible Cultural Heritage of Humanity. The Teotihuacan Pyramids: although it is very touristy, it is just a hop away from Mexico City and finds its way on many destination lists for a reason. A reminder of how fragile civilizations can be. What is your favorite taco? What mariachi song are you most likely to shout along to at 3 AM? AB: Favorite Taco: Taco de suadero (pronounced swa-day-ro), fatty, with meat caramelized in its own fat, tender, and—oh, did I say fatty? Note that Taco al Pastor is a staple among Mexico City’s delicious tacos. The meat on a rotating spit with its bright red/orange chili-based marinade (spicy but not hot) catches your eye. The way it is served with swiftly chopped charred pineapple for garnish adds to the visuals. A must-try! Mariachi song: I typically do not sing to these since they are dear to Mexican childhood memories, and I feel like an imposter if I do. However, Reggaetón is a highly dynamic genre that attracts many here in Mexico, not to forget salsa music. Don’t be surprised if you find yourself singing Daddy Yankee’s “Gasolina” from the top of your lungs while executing your best perreo or Luis Enrique’s “Yo no sé mañana” while a stranger takes you floating across the dance floor. If this is not the case, go to another party. I know I have. New Insights Members Torsten Schöneberg and Ines Liebscher present an interactive browser-based application, Splice-O-Mat, for understanding tissue distribution of alternatively spliced genes. PMID 38421639 Systematic assessment of the tethered agonist-dependent activities of all 33 aGPCRs in a suite of transcriptional reporter, G protein activation and B-arrestin recruitment assays. PMID: 38608683 The activation profile of different G proteins by ADGRL3 is shown using a collection of biosensor constructs. PMID: 38412860 GPR133 is hypomethylated and upregulated in decidual macrophages in recurrent spontaneous miscarriage patients. PMID: 38564758 BAI1 is expressed in the afferent spiral ganglion neurons in the mouse cochlea where it localizes AMPA receptors at the post-synaptic density and plays a crucial role in sound transmission. PMID: 38564333 CD97 expression is upregulated upon orthodontic compression and inhibits osteoclast differentiation, likely by Rap1a/ERK signaling pathway. PMID: 38311610 Member Dimitris Placantonakis’s identifies extended synaptotagmin 1 as an intracellular interaction partner of GPR133 using proximity labeling. PMID: 38758649 Member Simone Prömel’s lab shows that the nematode (C. elegans) homolog of CELSR, FMI-1, modulates the composition of the ECM and nematode body size. PMID: 38378098 Curated by Sumit J. Bandekar with help from Nathan Zaidman and Abhishek K. Singh

“The desire to take medicine is perhaps the greatest feature which distinguishes man from animals.” Sir William Osler Scientists have long sought to discover a “golden bullet” that would cure every disease without adverse effects. However, the journey to fine-tune human physiology is far from over. The more we know about the pathology of diseases, the more complicated it is to modulate them by a specific pathway without touching others. Notably, G-protein-coupled receptors (GPCRs), representing the biggest drug target, have been revealed to show functions through a plethora of signaling pathways. Historically, drug discovery efforts targeting GPCRs focused on G-protein-dependent signaling pathways, such as those involving cAMP and calcium mobilisation, to identify lead compounds. This emphasis may have caused other signaling pathways to be overlooked due to a need for adequate assay tools. While these signaling pathways are highly interconnected, they can also be regulated independently (Kenakin, 2019). Recent research has unveiled the emergence of G-protein-independent pathways, particularly those involving β-arrestins, which are now proving significant in drug discovery (Wei et al., 2003). β-arrestins, traditionally seen as terminators of G-protein signaling, are now recognised as critical players in activating extracellular signal-regulated kinases (ERK) pathways alongside the G-protein dependent pathways. This dual role opens new possibilities for more complex and nuanced cellular responses. Extracellular signal-regulated kinases (ERK), a subset of the mitogen-activated protein kinase (MAPK) family, have long been known to play a critical role in the signaling pathways of GPCRs. This signaling cascade involves several steps. Initially, the activation of small GTPases like RAS leads to the activation of the MAP kinase kinase kinases (MAPKKKs), such as RAF. RAF then phosphorylates and activates the MAP kinase kinases (MAPKKs), MEK1 and MEK2, which in turn phosphorylate and activate ERK1 and ERK2. Once activated, ERKs translocate to the nucleus, phosphorylating various transcription factors, including ETS, c-Jun, and Fos, modulating gene expression and influencing cellular functions (Lu & Malemud, 2019). ERK signaling, tightly regulated through feedback mechanisms and spatial localisation within the cell, is a crucial determinant of cellular responses such as proliferation, differentiation, migration, survival, growth, growth arrest and apoptosis. The gravity of this regulation becomes even more apparent when we consider the potential consequences of dysregulation. In various pathological conditions, including cancer, aberrant ERK activity can lead to uncontrolled cell proliferation and survival​, highlighting the pressing need to comprehend and control these pathways (Sugiura et al., 2021). ERK activation pathways can be categorised into two main sub-pathways based on their subcellular localisation: nuclear and cytosolic (Volmat & Pouysségur, 2001). The nuclear pathway typically involves ERK translocating into the nucleus to regulate gene expression, while the cytosolic pathway involves ERK acting in the cytoplasm to control other cellular functions. The choice of pathway can result in different cellular responses, underscoring the criticality of precise targeting in drug discovery. This further underscores the need for advanced assay technologies and a deep understanding of cellular signaling. Recently, several high-throughput screening (HTS) assays for ERK activation have been developed, each utilising different detection technologies. These include infrared fluorescence, electrochemiluminescence, fluorescence emission, immunofluorescence staining, HTRF (homogeneous time-resolved fluorescence), and TR-FRET (time-resolved fluorescence resonance energy transfer). Each assay offers unique advantages for detecting ERK activation, contributing to the broader toolkit available for GPCR-related drug discovery (Eishingdrelo & Kongsamut, 2013). In summary, targeting GPCR-activated ERK pathways represents a promising strategy for developing new therapeutics. By understanding the intricacies of GPCR signaling and utilising advanced assay technologies, researchers can identify novel drugs that selectively modulate this specific pathway, improving efficacy and safety profiles in clinical applications. References Eishingdrelo, H., & Kongsamut, S. (2013). Minireview: targeting GPCR activated ERK pathways for drug discovery. Current Chemical Genomics and Translational Medicine, 7, 9. Kenakin, T. (2019). Biased receptor signaling in drug discovery. Pharmacological Reviews, 71(2), 267-315. Lu, N., & Malemud, C. J. (2019). Extracellular Signal-Regulated Kinase: A Regulator of Cell Growth, Inflammation, Chondrocyte and Bone Cell Receptor-Mediated Gene Expression. International Journal of Molecular Sciences, 20(15). Sugiura, R., Satoh, R., & Takasaki, T. (2021). ERK: a double-edged sword in cancer. ERK-dependent apoptosis as a potential therapeutic strategy for cancer. Cells, 10(10), 2509. Volmat, V., & Pouysségur, J. (2001). Spatiotemporal regulation of the p42/p44 MAPK pathway. Biology of the Cell, 93(1‐2), 71-79. Wei, H., Ahn, S., Shenoy, S. K., Karnik, S. S., Hunyady, L., Luttrell, L. M., & Lefkowitz, R. J. (2003). Independent β-arrestin 2 and G protein-mediated pathways for angiotensin II activation of extracellular signal-regulated kinases 1 and 2. Proceedings of the National Academy of Sciences, 100(19), 10782-10787.

Hello everyone! Make sure you get our latest coverage of GPCRs for this week. We've got 15 insightful GPCR research papers and updates from the industry. Stay informed and up to date with the latest GPCR research and industry news. This week's highlight includes congrats to: John Teye Azietaku for his first contributor article on Illuminating GPCR Research: FRET and BRET-Based Sensors Shed Light on Cellular Signaling Abigail Walker, Aylin Hanyaloglu, et al., for their study on Constitutive internalisation of EP2 differentially regulates G protein signalling Ethan Dintzner, Demet Araç, et al. for their work on The far extracellular CUB domain of the adhesion GPCR ADGRG6/GPR126 is a key regulator of receptor signaling Jiankun Lyu, Brian Shoichet, Bryan Roth, et al. for their research on AlphaFold2 structures guide prospective ligand discovery Dr. GPCR University We launched the Dr.GPCR University workshop on Advanced Data Analysis for GPCR Pharmacology led by Dr. Sam Hoare three weeks ago, and it's been fantastic with all the participants from across the world. Mark your calendars for September and October 2024! We are excited to announce that Dr. Terry Kenakin will return with two back-to-back classes. Stay tuned for further details, as we plan to open registrations for both courses in July 2024. Dr. GPCR Podcast Exciting news! Episode 152 with Dr. Arthur Christopoulos is now live, titled "A Brief History of Allosteric Modulators." Dive into this fascinating topic and gain valuable insights from one of the leading experts in the field. Don't miss out—check it out now! And here's something even better: the video versions of our podcast episodes are now available to the public on our website! Re-watch your favorite episodes and catch up on any you have missed. Our most recent episode features our very own Dr. GPCR Board. Tune in and enjoy! Dr. GPCR Matchmaking Meet Mark Schmeizl, our Chief Matchmaker. Whether you’re hiring top talent or seeking a new career opportunity, Mark’s expertise ensures successful matches. Ready to get started? If you're looking to hire, fill out this form. If you want to be hired, fill out this form. And don’t miss our job opportunity spotlight for a Principal Scientist in In Vitro Pharmacology! Mark discussed this position with Beth Fleck, Director of In Vitro Pharmacology at Crinetics Pharmaceuticals! Dr. GPCR Symposia Explore GPCRs with our Premium Membership! Access recorded material from previous events, including the Dr. GPCR Summit editions. Our symposium on Structural Insights into GPCR Activation is postponed. Mark your calendar for the GPCRs as Therapeutic Targets symposium on October 11th, 2024. In the meantime, visit Dr. GPCR Symposia and learn from experts in the field. GPCR Event Highlight We are thrilled to announce our first in-person event in collaboration with the Adhesion GPCR Consortium: The 11th Adhesion GPCR Workshop, which will be held in vibrant Mexico City from October 23 to 25, 2024. Get ready to share your research with the global GPCR community! Submit your abstract using this form. We are also seeking sponsors to support this exciting event, which unites scientists worldwide to explore all facets of adhesion GPCR biology. If you're interested in sponsoring, please email us at Hello@DrGPCR.com. Let’s dive into the Classified GPCR News from May 13th to 19th, 2024. GPCR Activation and Signaling Constitutive internalisation of EP2 differentially regulates G protein signalling ArreSTick motif controls β-arrestin-binding stability and extends phosphorylation-dependent β-arrestin interactions to non-receptor proteins Identification of Gα12-vs-Gα13-coupling determinants and development of a Gα12/13-coupled designer GPCR GPR160 regulates the self-renewal and pluripotency of mouse embryonic stem cells via JAK1/STAT3 signal pathway A fluorescently-tagged tick kinin neuropeptide triggers peristalsis and labels tick midgut muscles The far extracellular CUB domain of the adhesion GPCR ADGRG6/GPR126 is a key regulator of receptor signaling GPCR Binders, Drugs, and more Silicon-Rhodamine Functionalized Evocalcet Probes Potently and Selectively Label Calcium Sensing Receptors In Vitro, In Vivo, and Ex Vivo GPCRs in Neuroscience Novel pharmacological targets for GABAergic dysfunction in ADHD GPCRs in Oncology and Immunology Exploration of prognostic and treatment markers in hepatocellular carcinoma via GPCR-related genes analysis Reviews, GPCRs, and more GPR56, an Adhesion GPCR with Multiple Roles in Human Diseases, Current Status and Future Perspective Structural and Molecular Insights into GPCR Function A homotrimeric GPCR architecture of the human cytomegalovirus revealed by cryo-EM Antibodies expand the scope of angiotensin receptor pharmacology Structural and dynamic insights into the activation of the μ-opioid receptor by an allosteric modulator Structural Insights into Partial Activation of the Prototypic G Protein-Coupled Adenosine A2A Receptor AlphaFold2 structures guide prospective ligand discovery Industry News Roche reports positive Phase Ib results for its dual GLP-1/GIP receptor agonist CT-388 in people with obesity Septerna to Present Preclinical Data from GPCR Drug Discovery Engine at ENDO 2024 𝐈𝐧𝐭𝐫𝐨𝐝𝐮𝐜𝐢𝐧𝐠 𝐀𝐋𝐋𝐎𝐃𝐃: 𝐀𝐥𝐥𝐨𝐬𝐭𝐞𝐫𝐲 𝐢𝐧 𝐃𝐫𝐮𝐠 𝐃𝐢𝐬𝐜𝐨𝐯𝐞𝐫𝐲 GPCR Events, Meetings, and Webinars May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 7, 2024 | Chemotactic Cytokines NEW June 4, 2024 | Live Webinar ‘It All Starts With a Protein – Protein Sciences as a Key to Success in Drug Discovery’ June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein Mediated Signaling Networks June 25 - 29, 2024 | FENS Forum 2024 October 2024 | Biologics US 2024 October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs HIGHLIGHT Principal Scientist, In vitro pharmacology NEW Senior Research Associate/Associate Scientist, Protein Science NEW Post-Doctoral Fellow—Pharmacology/Cell Biology/Biochemistry Post Doctoral Fellow Postdoc Position Senior Associate Scientist - Global Research Technologies Novo Nordisk Scientist I - Global Research Technologies Novo Nordisk Join Dr. GPCR Ecosystem

Human cells express over 800 G-protein-coupled receptors (GPCRs) to facilitate communication with the external environment. These receptors respond to a variety of signals by undergoing structural changes that activate internal G proteins, β-arrestins, and other transducers1. Capturing the dynamics of GPCR activation has always been a challenge because G protein activation in cells occurs in less than a second, reflecting the transient nature of these active states. A recent breakthrough study published in Nature by Makaía M. Papasergi-Scott and colleagues has made significant progress in this area 2. Using time-resolved cryo-electron microscopy (cryo-EM) and variability analysis to monitor the transitions of the Gs protein in complex with the β2-adrenergic receptor (β2AR) at brief sequential intervals following GTP addition, the research team identified the conformational changes that underlie G protein activation and its separation from the receptor. Twenty transition structures generated from overlapping particle subsets along this pathway provide a high-resolution description of the events driving G protein activation upon GTP binding. Unlike previous studies that provided only static snapshots, this approach captures the entire activation sequence in vivid detail. The captured structures reveal a dynamic of conformational changes initiated by the binding of an agonist isoproterenol to β2AR. This interaction significantly increases the receptor’s affinity for GTP, allowing a detailed observation of its interaction with the Gs protein in its activated state. From the initial GTP binding, the structures highlight critical shifts in the α5 helix and the α-helical domain (AHD) of the G protein. These alterations are essential for the complex mechanism of G protein activation, following GTP association with the Gα NTP binding pocket. The activation process begins with the α-helical domain (AHD) of the G protein in an open state, which is crucial for the initial binding of GTP. This early interaction sets the stage for a cascade of significant conformational changes. As GTP stabilizes and migrates towards the P loop, it causes the TCAT motif to shift, a key movement for the subsequent closure of the AHD. Concurrently, the α1 helix extends, propagating structural changes throughout the G protein. Further changes include the movement of Switch II towards the nucleotide-binding pocket and the stabilization of Switch III, both integral to the activation of the G protein. The AHD transitioning to a closed conformation prompts the β2–β3 loop to move away from the α5 helix, disrupting an ionic lock and allowing the α5 helix to start transitioning. This helix undergoes significant restructuring—it breaks and reforms closer to the TCAT motif, which is crucial for the final steps of G protein activation. This detailed process provided by the cryo-EM study offers a clear view of these dynamic states, from an inactive state (open AHD and GTP unbound) to an active state (closed AHD and GTP bound) and ultimately to the dissociation of the G protein from the receptor. This research not only deepens our understanding of a key biological process but also provides a valuable map for pharmaceutical researchers to design new therapies. With this high-resolution, dynamic view of GPCR activation, scientists can better tackle diseases by targeting specific steps within the G-protein activation cycle. This highlights the power of advanced imaging techniques like cryo-EM in solving complex biological puzzles and underscores the importance of understanding cellular processes at the molecular level for therapeutic advancements. Beyond GPCRs, the methods and insights from this study can be applied to other fast, transient biological processes. This approach is valuable for understanding the dynamics of other complex signaling pathways and molecular interactions, offering a deeper understanding of cellular processes at the molecular level. Premont, R. T. & Gainetdinov, R. R. Physiological roles of G protein-coupled receptor kinases and arrestins. Annu Rev Physiol 69, 511-534 (2007). Papasergi-Scott, M. M. et al. Time-resolved cryo-EM of G-protein activation by a GPCR. Nature (2024).

Hello everyone! Don't miss out on our latest coverage of GPCRs for this week. We have a total of 34 insightful GPCR research papers and seven updates from the industry. Stay informed and up to date with the latest GPCR research and industry news. This week's highlight includes congrats to: Drs. Sara Marsango and Graeme Milligan for their research on the Regulation of the pro-inflammatory G protein-coupled receptor GPR84 Drs. Chakit Arora, J Silvio Gutkind, and Francesco Raimondi for their work on The landscape of cancer-rewired GPCR signaling axes Affiong Ika Oqua, Dr. Alejandra Tomas, et al. for their study on Lipid regulation of the glucagon receptor family Drs. Naveen Thakur, Kenneth A Jacobson, Matthew T Eddy, et al. for their analysis on Membrane mimetic-dependence of GPCR energy landscapes Dr. GPCR University We successfully started our Dr.GPCR University workshop, 'Advanced Data Analysis for GPCR Pharmacology,’ led by Dr. Sam Hoare. Mark your calendar for September and October 2024. Dr. Kenakin will be back with two back-to-back classes. Stay tuned as we plan to open registrations for both classes in July 2024. Dr. GPCR Podcast Episode #151 is out! A special episode with our board, meet Drs. Maria Waldhoer, JoAnn Trejo, and Anne Marie Quinn. Did you watch Episode #150 of the Dr. GPCR Podcast? Join us in this episode to meet the team behind Dr. GPCR, hear anecdotes, and get important announcements. Tune in and be the first to know about the benefits coming your way! Dr. GPCR Matchmaking Mark Schmeizl, our Chief Matchmaker, can help you find your perfect match if you want to hire or be hired. Mark has experience connecting candidates with employers and will work with you to understand your needs and preferences to ensure a successful match. Contact Mark today to get started. Dr. GPCR Symposia Learn more about GPCRs by signing up for a Premium Membership to watch all the material recorded at our previous events, including the three editions of the Dr. GPCR Summit. We have postponed our symposium on Structural Insights into GPCR Activation to a later date. Stay tuned for our next symposium on GPCRs as Therapeutics Targets on October 11th, 2024. In the meantime, visit Dr. GPCR Symposia and learn from experts in the field. GPCR Event Highlight We are thrilled to partner with the Adhesion GPCR Consortium to organize our first Dr. GPCR in-person event. Mark your calendar for October 23 - 25, 2024, as we kick off the 11th Adhesion GPCR Workshop in Mexico City. Abstract submissions and registrations will open soon. Stay tuned We are also looking for sponsors to help support this fabulous event that brings together scientists worldwide working on all aspects of adhesion GPCR biology. Please reply to this email if you'd like to sponsor this event. Let’s dive into the Classified GPCR News from April 29th to May 12th, 2024 Adhesion GPCRs Essential Role of Latrophilin-1 Adhesion GPCR Nanoclusters in Inhibitory Synapses Embryonic spatiotemporal expression pattern of Folded gastrulation suggests roles in multiple morphogenetic events and regulation by AbdA GPCR Activation and Signaling The critical importance of conditions: Reconciling GPCR functionality and biophysical findings Adrenoceptor Desensitization: Current Understanding of Mechanisms Biased agonists of GPR84 and insights into biological control GPR84 in physiology-Many functions in many tissues Regulation of the pro-inflammatory G protein-coupled receptor GPR84 Function and regulation of GPR84 in human neutrophils Large-scale deorphanization of Nematostella vectensis neuropeptide G protein-coupled receptors supports the independent expansion of bilaterian and cnidarian peptidergic systems GPCR Binders, Drugs, and more A relaxin receptor gene RpGPCR41 is involved in the resistance of Rhopalosiphum padi to pyrethroids Discovering allatostatin type-C receptor specific agonists Discovery of the Clinical Candidate IDOR-1117-2520: A Potent and Selective Antagonist of CCR6 for Autoimmune Diseases MRGPRX4 mediates phospho-drug-associated pruritus in a humanized mouse model GPCRs in Cardiology, Endocrinology, and Taste The Genetic Pathophysiology and Clinical Management of the TADopathy, X-Linked Acrogigantism Thrombosis With Thrombocytopenia and Post-COVID-Vaccination Syndrome With Anti-G-Protein-Coupled Receptor (GPCR) Antibodies Treated With Therapeutic Plasma Exchange SUCNR1 regulates insulin secretion and glucose elevates the succinate response in people with prediabetes GPCRs in Neuroscience Spatiotemporal organization of prefrontal norepinephrine influences neuronal activity Transient cAMP production drives rapid and sustained spiking in brainstem parabrachial neurons to suppress feeding The C-terminus of the prototypical M2 muscarinic receptor localizes to the mitochondria and regulates cell respiration under stress conditions GPCRs in Oncology and Immunology Wnt pathway inhibition with the porcupine inhibitor LGK974 decreases trabecular bone but not fibrosis in a murine model with fibrotic bone The orphan G protein-coupled receptor 141 expressed in myeloid cells functions as an inflammation suppressor The landscape of cancer-rewired GPCR signaling axes Methods & Updates in GPCR Research ONE-GO: Direct detection of context-dependent GPCR activity Author Correction: GPCR molecular dynamics forecasting using recurrent neural networks Glycoprotein-glycoprotein receptor binding detection using bioluminescence resonance energy transfer Bayesian network models identify cooperative GPCR:G protein interactions that contribute to G protein coupling Reviews, GPCRs, and more Molecular adaptations in response to exercise training are associated with tissue-specific transcriptomic and epigenomic signatures Lipid regulation of the glucagon receptor family Technologies for the discovery of G protein-coupled receptor-targeting biologics Lipid mediators in neutrophil biology: inflammation, resolution and beyond Exploring GPCR signaling pathway networks as cancer therapeutic targets Generation of comprehensive GPCR-transducer-deficient cell lines to dissect complexity of GPCR signaling Structural and Molecular Insights into GPCR Function Membrane mimetic-dependence of GPCR energy landscapes Structural and Computational Insights into Dynamics and Intermediate States of Orexin 2 Receptor Signaling Industry News Addex Gets Creative To Secure Funding And Its Future Reunion Neuroscience Inc. Announces $103 Million Series A Financing Co-Led by MPM BioImpact and Novo Holdings Neurocrine Biosciences Announces Initiation of Phase 1 Clinical Study Evaluating Effects of NBI-1117567 in Healthy Adults Crinetics Pharmaceuticals Reports First Quarter 2024 Financial Results and Provides Business Update Nxera Pharma Operational Highlights and Consolidated Results for the First Quarter 2024 Crinetics Pharmaceuticals To Present Advancements From Atumelnant (Crn04894) And Paltusotine Development Programs At Endo 2024 Exscientia's CEO shares a pipeline overview and learnings from being one of the first AI companies out front and to go public GPCR Events, Meetings, and Webinars May 13 - 17, 2024 | 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 7, 2024 | Chemotactic Cytokines June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein Mediated Signaling Networks June 25 - 29, 2024 | FENS Forum 2024 July 8 - 10, 2024 | 4th IRN i-GPCRnet Annual October 2024 | Biologics US 2024 October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs Post Doctoral Fellow Postdoc Position Principal Scientist, In vitro Pharmacology Senior Associate Scientist - Global Research Technologies Novo Nordisk Scientist I - Global Research Technologies Novo Nordisk Postdoctoral Associate Research Technologist I Join Dr. GPCR Ecosystem

G protein-coupled receptors (GPCRs) are integral membrane proteins crucial for sensing extracellular signals, including hormones, neurotransmitters, and environmental cues. These receptors initiate intracellular signaling cascades upon activation, ultimately regulating a myriad of physiological processes. Central to GPCR function are G proteins, comprising subfamilies such as Gs, Gi/o, Gq/11, and G12/13, which orchestrate downstream signaling events, including the modulation of cyclic adenosine monophosphate (cAMP), calcium mobilization, and extracellular signal-regulated kinase (ERK) activation [1]. Traditionally, second messenger assays measuring cAMP accumulation, calcium mobilization, and ERK phosphorylation have been pivotal in deciphering GPCR activity, particularly in drug discovery endeavors [2]. However, these conventional assays often provide limited information on intermediate signaling events due to pathway crosstalk and signal amplification [3]. Also, most second messenger assays are primarily endpoint measurements and do not allow practical measurement of the kinetics of signaling. The emergence of resonance energy transfer (RET) techniques, notably Fluorescence Resonance Energy Transfer (FRET) and Bioluminescence Resonance Energy Transfer (BRET), has revolutionized the study of GPCRs by enabling real-time monitoring of protein-protein interactions and intracellular signaling dynamics[4]. FRET and BRET sensors operate on the principle of energy transfer between a fluorescent or luminescent donor and acceptor molecules within close proximity, typically within 100Å. These biosensors have facilitated the investigation of various aspects of GPCR signaling, including ligand binding (e.g NanoBRET ligand binding [5]), effector protein recruitment assays (e.g G protein recruitment assay [6], mini-G recruitment assay [7], GRK and β-arrestin recruitment assays [8]), G protein activation (e.g TRUPATH assay [9]), receptor trafficking ( e.g FYVE assay [10]),  β-arrestin dynamics ( e.g FLAsH biosensor [11]), cAMP production (e.g CAMYEL assay [12]) , and ERK activity (e.g YEN assay [13]), among others. One of the significant advantages of FRET and BRET-based sensors is their ability to provide real-time readouts of pharmacological activity, allowing for the determination of drug kinetics—a critical aspect in drug development [14]. Moreover, these experiments can be conducted in live cells, preserving the physiological context and minimizing artifacts associated with sample preparation for endpoint measurements. Despite their immense potential, utilizing FRET and BRET sensors in GPCR research comes with challenges, including expensive cost of reagents, optimizing sensor expression levels and adapting these systems to disease-relevant models. Addressing these hurdles is essential for translating findings from cellular models to clinically relevant scenarios. Some innovative solutions have been the development of the BERKY and the ONE-GO biosensors, designed to facilitate their application in disease models[3, 15]. BERKY consists of a membrane linker, a BRET donor, an ER/K α-helix linker, a BRET acceptor, and an active G protein detector. The ONE-GO biosensors, designed in a single vector, incorporate a G protein tagged with a YFP acceptor and a G protein detector tagged with an Nluc donor. Both BERKY and ONE-GO biosensors are engineered to detect the GTP-bound Gα subunit, serving as a proxy for G protein activation and have been optimized for use in detecting GPCR activity in primary cells. In conclusion, FRET and BRET-based sensors have transformed the landscape of GPCR research, offering unprecedented insights into the intricacies of GPCR signaling. These techniques not only enhance our understanding of fundamental cellular processes, but also hold immense promise in accelerating drug discovery efforts by enabling the precise characterization of pharmacological interventions in real time. As technology continues to advance, leveraging RET-based sensors will undoubtedly continue to propel our quest to unravel the complexities of GPCR signaling and pave the way for novel therapeutic strategies. 1.      Gilman, A.G., G proteins: transducers of receptor-generated signals. Annu Rev Biochem, 1987. 56: p. 615-49. 2.      Zhou, Y., et al., Multiple GPCR Functional Assays Based on Resonance Energy Transfer Sensors. Front Cell Dev Biol, 2021. 9: p. 611443. 3.      Maziarz, M., et al., Revealing the Activity of Trimeric G-proteins in Live Cells with a Versatile Biosensor Design. Cell, 2020. 182(3): p. 770-785.e16. 4.      Salahpour, A., et al., BRET biosensors to study GPCR biology, pharmacology, and signal transduction. Frontiers in Endocrinology, 2012. 3. 5.      Zhao, P., et al., Activation of the GLP-1 receptor by a non-peptidic agonist. Nature, 2020. 577(7790): p. 432-436. 6.      Galés, C., et al., Real-time monitoring of receptor and G-protein interactions in living cells. Nat Methods, 2005. 2(3): p. 177-84. 7.      Wan, Q., et al., Mini G protein probes for active G protein-coupled receptors (GPCRs) in live cells. J Biol Chem, 2018. 293(19): p. 7466-7473. 8.      McNeill, S.M., et al., The role of G protein-coupled receptor kinases in GLP-1R β-arrestin recruitment and internalisation. Biochemical Pharmacology, 2024. 222: p. 116119. 9.      Olsen, R.H.J., et al., TRUPATH, an open-source biosensor platform for interrogating the GPCR transducerome. Nat Chem Biol, 2020. 16(8): p. 841-849. 10.    Namkung, Y., et al., Monitoring G protein-coupled receptor and β-arrestin trafficking in live cells using enhanced bystander BRET. Nature Communications, 2016. 7(1): p. 12178. 11.    Strungs, E.G., L.M. Luttrell, and M.H. Lee, Probing Arrestin Function Using Intramolecular FlAsH-BRET Biosensors. Methods Mol Biol, 2019. 1957: p. 309-322. 12.    Jiang, L.I., et al., Use of a cAMP BRET sensor to characterize a novel regulation of cAMP by the sphingosine 1-phosphate/G13 pathway. J Biol Chem, 2007. 282(14): p. 10576-84. 13.    Goyet, E., et al., Fast and high resolution single-cell BRET imaging. Sci Rep, 2016. 6: p. 28231. 14.    Pfleger, K.D., R.M. Seeber, and K.A. Eidne, Bioluminescence resonance energy transfer (BRET) for the real-time detection of protein-protein interactions. Nat Protoc, 2006. 1(1): p. 337-45. 15.    Janicot, R., et al., Direct interrogation of context-dependent GPCR activity with a universal biosensor platform. bioRxiv, 2024.

Hello readers! We got a little busy with all the major events at Dr.GPCR, so our weekly news looks slightly different. We will be back next week with our regular weekly GPCR news digest. In the meantime, you can always check the  Classified GPCR News from the last weeks. Today, we celebrate a huge milestone by releasing Episode #150 of the Dr. GPCR Podcast. Join us in this wonderful episode to meet the team of volunteers behind the work you see. The story behind how Dr.GPCR came to be, the people behind the process, the great anecdotes, and what’s coming next. We also have some important announcements in today’s episode, so join us in this celebration and be the first to know about all the changes coming to Dr. GPCR. Today is also the first session of our hands-on workshop with Dr. Sam Hoare. If you aren't joining us this time, stay tuned for more Dr. GPCR University content coming soon.

Hello readers! Check out our GPCR coverage for this week. We have 15 GPCR papers, two industry news, and one job ad. This week's highlight includes congrats to: André Nguyen Dietzsch, Simone Prömel, et al. for their work on the Dysfunction of the adhesion GPCR latrophilin 1 (ADGRL1/LPHN1) increases the risk of obesity Norton Cheng, JoAnn Trejo, et al. for their research on Ubiquitin-driven GPCR Inflammatory Signaling at the Endosome Dr. GPCR University Hurry! Only five spots left! Team Registrations are also open!  You have until 5 pm EST tomorrow to register. We are pleased to announce five full scholarship opportunities for Dr. Hoare's workshop for individuals who live and work in developing countries. Please complete this form to take advantage of this opportunity on a first-come, first-served basis. We also ask that you share this with your colleagues. We define a developing country based on World Bank Classifications for its 2024 fiscal year. Join our upcoming Dr. GPCR University hands-on workshop with Dr. Samuel Hoare on Advanced data analysis for GPCR pharmacology, which will be held on Thursdays between May 9th and May 30th, 2024, from 10 am to 12 pm EDT. The workshop includes: Four x 2-hour Zoom sessions One-on-one meeting with Dr. Hoare Access to Dr. GPCR Ecosystem group Access to course materials and recordings Completion certificate One-year Dr. GPCR Ecosystem Premium Membership (restrictions apply) Early bird discount on future courses (restrictions apply) Dr. GPCR Symposia Join us on June 7th for our symposium on Structural and Molecular Insights into GPCR Function. Stay tuned for more details. Premium members get access to on-demand content from past events. Submit a few slides for a poster presentation to showcase your research and network with our community. Fill out this form to get started! Remember to give us your feedback by completing our survey if you've participated in our symposiums. Dr. GPCR Matchmaking Did you check out our first job opportunity spotlight for a Principal Scientist In Vitro Pharmacology? Our Chief Matchmaker, Mark Schmeizl, had a great conversation about this position with Beth Fleck, Director of In Vitro Pharmacology at Crinetics Pharmaceuticals! Don't miss out! Also, Mark Schmeizl can help you find your perfect match if you want to hire or be hired. Mark has experience connecting candidates with employers and will work with you to understand your needs and preferences to ensure a successful match. Contact Mark today to get started. Let’s dive into the Classified GPCR News from April 22nd to 28th, 2024 Adhesion GPCRs Dysfunction of the adhesion G protein-coupled receptor latrophilin 1 (ADGRL1/LPHN1) increases the risk of obesity GPCR Activation and Signaling Variable CGRP family peptide signaling durations and the structural determinants thereof Ubiquitin-driven G Protein-Coupled Receptor Inflammatory Signaling at the Endosome GPCR Binders, Drugs, and more Discovery and development of macrocyclic peptide modulators of the cannabinoid 2 receptor GPCRs in Cardiology, Endocrinology, and Taste Discovery of a SUCNR1 antagonist for potential treatment of diabetic nephropathy: In silico and in vitro studies GPCRs in Neuroscience Phytocannabinoids in neuromodulation: from omics to epigenetics The receptor tyrosine kinase IGF1R and its associated GPCRs are co-regulated by the noncoding RNA NEAT1 in Alzheimer's disease Parenting behaviors in mice: Olfactory mechanisms and features in models of autism spectrum disorders Systematic characterization of multi-omics landscape between gut microbial metabolites and GPCRome in Alzheimer's disease Methods & Updates in GPCR Research Single-chain fluorescent integrators for mapping G-protein-coupled receptor agonists Development of a synthetic relaxin-3/INSL5 chimeric peptide ligand for NanoBiT complementation binding assays Generation of a deep mouse brain spectral library for transmembrane proteome profiling in mental disease models Reviews, GPCRs, and more The nematode-trapping fungus Arthrobotrys oligospora detects prey pheromones via G protein-coupled receptors Structural and Molecular Insights into GPCR Function Fungal alkaloid malbrancheamide reorients the lipid binding domain of GRK5 Molecular Determinant Underlying Selective Coupling of Primary G-Protein by Class A GPCRs Industry News Introducing Big Sky BacMam Chemical tool illuminates pathways used by dopamine, opioids and other neuronal signals GPCR Events, Meetings, and Webinars May 13 - 17, 2024 | 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 7, 2024 | Chemotactic Cytokines June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein Mediated Signaling Networks June 25 - 29, 2024 | FENS Forum 2024 NEW July 8 - 10, 2024 | 4th IRN i-GPCRnet Annual October 2024 | Biologics US 2024 October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs NEW Post Doctoral Fellow Postdoc Position Principal Scientist, In vitro pharmacology Senior Associate Scientist - Global Research Technologies Novo Nordisk Scientist I - Global Research Technologies Novo Nordisk Postdoctoral Associate Research Technologist I Senior Scientist- Internal Medicine Research Unit Postdoctoral Scholar – Synaptic physiology, optical imaging, substance use disorder, pharmacology Join Dr. GPCR Ecosystem

Hello there! We have some exciting updates for all the GPCR enthusiasts out there. This week, we have a comprehensive coverage of 12 GPCR research papers. Additionally, we have six industry news. And if you're looking for a new job opportunity, we have one job ad. This week's highlight includes congrats to: Luca Franchini and Cesare Orlandi for their research on Deorphanization of G Protein Coupled Receptors (GPCRs): a historical perspective Monserrat Avila-Zozaya article on From DNA day to GPCR genomics Dr. GPCR University Hurry! 17 out of the 25 spots have been filled! Team Registrations are also available!  You have until May 3rd, 2023 to register. We are pleased to announce five full scholarship opportunities for Dr. Hoare's workshop for individuals who live and work in developing countries. Please complete this form to take advantage of this opportunity on a first-come, first-served basis. We also ask that you share this with your colleagues. We define a developing country based on World Bank Classifications for its 2024 fiscal year. Join our upcoming Dr. GPCR University hands-on workshop with Dr. Samuel Hoare on Advanced data analysis for GPCR pharmacology, which will be held on Thursdays between May 9th and May 30th, 2024, from 10 am to 12 pm EDT. The workshop includes: Four x 2-hour Zoom sessions One-on-one meeting with Dr. Hoare Access to Dr. GPCR Ecosystem group Access to course materials and recordings Completion certificate One-year Dr. GPCR Ecosystem Premium Membership (restrictions apply) Early bird discount on future courses (restrictions apply) Check our conversation with Dr. Sam Hoare about this hands-on workshop HERE ⬇⬇⬇ Dr. GPCR Symposia Join us on June 7th for our symposium on Structural and Molecular Insights into GPCR Function. Stay tuned for more details. Premium members get access to on-demand content from past events. Submit a few slides for a poster presentation to showcase your research and network with our community. Fill out this form to get started! Don't forget to give us your feedback by completing our survey if you've participated in our symposiums. Dr. GPCR Matchmaking Did you check out our first job opportunity spotlight for a Principal Scientist In Vitro Pharmacology? Our Chief Matchmaker, Mark Schmeizl, had a great conversation about this position with Beth Fleck, Director of In Vitro Pharmacology at Crinetics Pharmaceuticals! Don't miss out! Also, if you are looking to hire or be hired, Mark Schmeizl can help you find your perfect match. Mark has experience connecting candidates with employers and will work with you to understand your needs and preferences to ensure a successful match. Contact Mark today to get started. Let’s dive into the Classified GPCR News from April 15th to 21st, 2024 GPCR Activation and Signaling Beneath the surface: endosomal GPCR signaling The M3 muscarinic acetylcholine receptor can signal through multiple G protein families Rapid elucidation of agonist-driven regulation of the neurokinin 1 receptor using a GPCR phosphorylation immunoassay GPCR Binders, Drugs, and more Identification of 1,3,8-triazaspiro[4.5]decane-2,4-dione Derivatives as a Novel Delta Opioid Receptor-Selective Agonist Chemotype GPCRs in Neuroscience Calcium-sensing receptor regulates Kv7 channels via Gi/o protein signalling and modulates excitability of human induced pluripotent stem cell-derived nociceptive-like neurons Characterization of myoinhibitory peptide signaling system and its implication in larval metamorphosis and spawning behavior in Pacific abalone The role of orphan G protein-coupled receptors in pain GPCRs in Oncology and Immunology Deciphering a GPCR-lncRNA-miRNA Nexus: Identification of an Aberrant Therapeutic Target in Ovarian Cancer Methods & Updates in GPCR Research Alared: Solvatochromic and Fluorogenic Red Amino Acid for Ratiometric Live-cell Imaging of Bioactive Peptides Cascaded amplifying circuit enables sensitive detection of fungal pathogens In Silico Analyses of Vertebrate G-Protein-Coupled Receptor Fusions United With or Without an Additional Transmembrane Sequence Indicate Classification into Three Groups of Linkers Reviews, GPCRs, and more Deorphanization of G Protein Coupled Receptors (GPCRs): a historical perspective Industry News Addex Therapeutics Reports Full Year 2023 Financial Results And Provides Corporate Update Aelis Farma announces the Last Patient, Last Visit in its clinical phase 2b trial with AEF0117 for the treatment of cannabis use disorder Orion Biotechnology will be presenting at the 19th Biopharma Drug Discovery Nexus Salipro Biotech will participate in BioKorea2024 Domain Therapeutics Appoints Sean A. MacDonald as Chief Executive Officer Nxera Pharma Announces Exclusive Supply and Distribution Agreement with Handok for PIVLAZ™ in South Korea Amgen To Present Tezspire® Phase 2A COPD Data At ATS 2024 GPCR Events, Meetings, and Webinars April 17 – May 1, 2024 | FREE ASPET Virtual Award Lecture Series May 13 - 17, 2024 | 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 7, 2024 | Chemotactic Cytokines June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein Mediated Signaling Networks June 25 - 29, 2024 | FENS Forum 2024 October 2024 | Biologics US 2024 October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs NEW Postdoc Position Principal Scientist, In vitro pharmacology Senior Associate Scientist - Global Research Technologies Novo Nordisk Scientist I - Global Research Technologies Novo Nordisk Postdoctoral Associate Research Technologist I Senior Scientist- Internal Medicine Research Unit Postdoctoral Scholar – Synaptic physiology, optical imaging, substance use disorder, pharmacology Join Dr. GPCR Ecosystem

Hello Dr. GPCR ecosystem members!  As Chief Matchmaker, I recently had the pleasure of speaking with Beth Fleck, Director of In Vitro Pharmacology at Crinetics Pharmaceuticals.  Beth is also the hiring manager for their open Principal Scientist, In Vitro Pharmacology role posted in the Dr. GPCR ecosystem.  Our conversation provided additional insight you cannot find in a job description, so I thought I’d share this insight with you. Mark:  “Beth, why did you decide to join Crinetics?” Beth:  “I was invited to join Crinetics a few years ago by some former colleagues and their description of the company was very intriguing: a biology focused, small molecule focused, smaller drug discovery company with a great work environment.  Crinetics hires people with big brains and small egos.” Mark:  “Have you found this to be accurate?” Beth:  “Yes.  There are a lot of learning opportunities at Crinetics.  We collaborate and cross-pollenate a lot.” Mark:  “So, what are the qualities of the perfect candidate for the Principal Scientist role?” Beth:  “We are looking for a thinker and problem solver who is able to learn.  Someone with strong assay development skills as well as strong data analysis and interpretation skills.” Mark:  “Are there particular assay types of interest?” Beth:  “We focus on biochemical, cell based, and radioligand binding assays to enable SAR, MOA, lead optimization, and new target discovery.  Top candidates will have a solid foundation in GPCR pharmacology as well as some experience in drug discovery.” Mark:  “Beth, why would someone want you as their boss?” Beth:  “Well, I enjoy training and mentoring team members.  I keep an open door and you’ll find me among the team in the lab quite often.  There’s comradery and open exchange in our team and I strive to provide learning opportunities for career development.” So, if you are looking for an on-site opportunity in San Diego and Beth’s comments sound good to you, please reach out to me at mschmeizl@grnwindsor.com or 860-325-3505 and we can dig a bit deeper. By: Mark Schmeizl Chief Matchmaker at Dr. GPCR

Hello readers! Check out our GPCR coverage for this week. We have 15 GPCR papers, three industry news, one event, and one job ad. This week's highlight includes congrats to: Tessa de Vries, Graham Ladds, Antoinette MaassenVanDenBrink, et al. for their work on Intracellular pathways of calcitonin gene-related peptide-induced relaxation of human coronary arteries: A key role for Gβγ subunit instead of cAMP. Katharina Grotsch, Bryan L Roth, Valery V Fokin  et al. for their research on Virtual Screening of a Chemically Diverse "Superscaffold" Library Enables Ligand Discovery for a Key GPCR Target Gunnar Schulte, Lukas Grätz, Pawel Kozielewicz, et al. for their study on Frizzleds act as dynamic pharmacological entities Marina Casiraghi, Robert J Lefkowitz, Peter Gmeiner, Brian K Kobilka et al. for their investigation on Molecular insights into G protein coupling specificity at a class A GPCR Jianjun Cao, Arthur Christopoulos, Patrick M. Sexton et al. for their job on Cryo-EM Structure of the Human Amylin 1 Receptor in Complex with CGRP and Gs Protein Dr. GPCR University Hurry! 11 out of the 25 spots have been filled! Team Registrations are also available! Early bird registration ends TODAY. Join our upcoming Dr. GPCR University hands-on workshop with Dr. Samuel Hoare on Advanced data analysis for GPCR pharmacology, which will be held on Thursdays between May 9th and May 30th, 2024, from 10 am to 12 pm EDT. The workshop includes: Four x 2-hour Zoom sessions One-on-one meeting with Dr. Hoare Access to Dr. GPCR Ecosystem group Access to course materials and recordings Completion certificate One-year Dr. GPCR Ecosystem Premium Membership (restrictions apply) Early bird discount on future courses (restrictions apply) Save 25% with early bird registration that ends TODAY!! We are pleased to announce five full scholarship opportunities for Dr. Hoare's workshop for individuals who live and work in developing countries. Please complete this form to take advantage of this opportunity. It's on a first-come, first-served basis. We also ask that you share this with your eligible colleagues. We define a developing country based on World Bank Classifications for its 2024 fiscal year. Check our conversation with Dr. Sam Hoare about this hands-on workshop HERE ⬇⬇⬇ Dr. GPCR Symposia Join us on June 7th for our next symposium on Structural and Molecular Insights into GPCR Function. Stay updated for more details. Do you want to re-watch our recorded events? As a premium member, access on-demand content from past Dr. GPCR Symposiums and much more! If you have any research you would like to showcase to our community, you can submit a poster presentation. It doesn’t have to be a complete poster, just a few slides to spark the conversation. This is an excellent opportunity to network and increase your visibility on our platform. To begin, please fill out this form! If you've participated in our symposiums, please take a few minutes to complete this survey. Your feedback is valuable to us. Dr. GPCR Partnered Events April 22 - 23, 2024 | Endocrine Metabolic GPCRs Join the Endocrine Metabolic GPCRs event in Birmingham, UK, on April 22-23, 2024. Let’s dive into the Classified GPCR News from April 8th to 14th, 2024 Adhesion GPCRs High incidence of imperforate vagina in ADGRA3-deficient mice GPCR Activation and Signaling Local anesthetics inhibit muscarinic acetylcholine receptor-mediated calcium responses and the recruitment of β-arrestin in HSY human parotid cells GPCR kinase subtype requirements for arrestin-2 and -3 translocation to the cannabinoid CB1 receptor and the consequences on G protein signalling Melanin-concentrating hormone receptor 1 is discarded by exosomes after internalization Intracellular pathways of calcitonin gene-related peptide-induced relaxation of human coronary arteries: A key role for Gβγ subunit instead of cAMP GPCR Binders, Drugs, and more Virtual Screening of a Chemically Diverse "Superscaffold" Library Enables Ligand Discovery for a Key GPCR Target GPCRs in Cardiology, Endocrinology, and Taste Orphan GPCR GPRC5C Facilitates Angiotensin II-Induced Smooth Muscle Contraction GPCRs in Neuroscience Evolutionary origins of bitter taste receptors in jawed vertebrates Methods & Updates in GPCR Research Exploring GPCR conformational dynamics using single-molecule fluorescence Droplet-based microfluidic platform for detecting agonistic peptides that are self-secreted by yeast expressing a G-protein-coupled receptor Reviews, GPCRs, and more The GLP-1R as a model for understanding and exploiting biased agonism in next-generation medicines G protein-coupled receptors (GPCRs): advances in structures, mechanisms, and drug discovery Frizzleds act as dynamic pharmacological entities Structural and Molecular Insights into GPCR Function Molecular insights into G protein coupling specificity at a class A GPCR Cryo-EM Structure of the Human Amylin 1 Receptor in Complex with CGRP and Gs Protein Industry News Monash University retains its N° 2 global ranking for Pharmacy and Pharmacology Addex Therapeutics to Release Full-Year 2023 Financial Results and Host Conference Call on April 18, 2024 Nxera Pharma Notes Successful Development Progress of Partnered Schizophrenia Candidate NBI-1117568 GPCR Events, Meetings, and Webinars NEW April 17 – May 1, 2024 | FREE ASPET Virtual Award Lecture Series May 13 - 17, 2024 | 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 7, 2024 | Chemotactic Cytokines June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein Mediated Signaling Networks June 25 - 29, 2024 | FENS Forum 2024 October 2024 | Biologics US 2024 October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs NEW Principal Scientist, In vitro pharmacology Senior Associate Scientist - Global Research Technologies Novo Nordisk Scientist I - Global Research Technologies Novo Nordisk Postdoctoral Associate Research Technologist I Senior Scientist- Internal Medicine Research Unit Postdoctoral Scholar – Synaptic physiology, optical imaging, substance use disorder, pharmacology Research Fellow Join Dr. GPCR Ecosystem

April is the month of DNA Day, a special day commemorating the discovery of the DNA double helix structure in 1953 and the completion of the Human Genome Project in 2003. In the United States, DNA Day was officially celebrated on April 25th, 2003. Since then, the National Human Genome Research Institute (NHGRI) has supported annual events across the country to celebrate, learn and discuss the latest advances in genomic research. Eventually, April 25th was declared and recognized as International DNA Day1. What does DNA Day have to do with GPCRs? The discovery of DNA's double helical structure was a scientific milestone that revolutionized molecular biology. It provided a fundamental understanding of how genetic information is stored and transferred between generations. This breakthrough also paved the way for the development of genomics, a field of study that examines an organism's entire DNA or genome, including its genes, regulatory elements, and non-coding DNA sequences. Genomics, in turn, played a crucial role in the discovery and sequencing of the beta-adrenergic receptor (βAR), the first GPCR to be identified by Robert Lefkowitz and colleagues during their study of the effects of adrenaline on cells2. This intersection of genomics and GPCR research sparked a new era of a comprehensive understanding of GPCR biology, the development of GPCR-targeted drugs, and the exploration of GPCRs as key regulators of physiological processes and therapeutic targets in medicine. The completion of the Human Genome Project revealed that GPCR genes in the human genome range from approximately 800 to over 1,000. This variation is due to factors such as alternative splicing, gene duplications, and variability in genomic methods. However, it's worth noting that the total count of GPCR genes in the human genome is still being refined as genome sequencing technologies and bioinformatics tools improve. Also, ongoing research may discover new GPCRs or refine existing data, which could lead to adjustments in the total count of GPCR genes in the human genome. Additionally, genomic approaches such as transcriptomics and proteomics have provided insights into the expression patterns and post-translational modifications of GPCRs under different physiological conditions3. Another significant impact of genomics on GPCR research is the elucidation of receptor structure and function. Advances in structural genomics, coupled with techniques like X-ray crystallography and cryo-electron microscopy, have allowed us to understand the structural dynamics during receptor activation. Thanks to recent scientific advances, we now have a better understanding of the structural changes that happen when a receptor is activated. For example, we know that transmembrane helices move during receptor activation and that the DRY motif plays a vital role in activating G-proteins and binding to B-arrestin4. Additionally, there have been recent discoveries of the conformational changes that occur during G-protein activation by the β2-adrenergic receptor, using a time-resolved approach5. Furthermore, computational genomics approaches, such as structural bioinformatics analysis, have facilitated drug discovery and design targeting GPCRs, leading to the development of novel therapeutics. Advances in genomic technologies, such as genome-wide association studies and next-generation sequencing, have enabled the uncovering of associations between GPCR genetic variants and diseases. The genetic variation in GPCRs is extensive; databases like GPCRdb provide a large database of genetic variations (including single nucleotide polymorphisms or SNPs) that may impact the structure or function of GPCRs. For example over 160 SNPs have been reported for the β2AR gene, with some of these SNPs having clinical significance. Another example is the cannabinoid receptor 1 with a total of 248 SNPs, where 190 missense mutations were predicted to have a functional effect4. Overal, genomics has been a driving force in advancing scientific knowledge and innovation within the GPCR world. The integration of genomics with structural biology, pharmacology, bioinformatics, and clinical research has opened new avenues for exploring GPCR biology, developing targeted therapies, and translating genomic discoveries into clinical practice. As we celebrate Happy DNA Day, it's a testament to how genomics has revolutionized our understanding of GPCRs and their role in human health. References National Human Genome Research Institute, U. S. (2002) National Human Genome Research Institute. United States. https://www.genome.gov/ Dixon, R. A., Kobilka, B. K., Strader, D. J., Benovic, J. L., Dohlman, H. G., Frielle, T., Bolanowski, M. A., Bennett, C. D., Rands, E., Diehl, R. E., Mumford, R. A., Slater, E. E., Sigal, I. S., Caron, M. G., Lefkowitz, R. J., & Strader, C. D. (1986). Cloning of the gene and cDNA for mammalian beta-adrenergic receptor and homology with rhodopsin. Nature, 321(6065), 75–79. https://doi.org/10.1038/321075a0 Fredriksson, R., Lagerström, M. C., Lundin, L. G., & Schiöth, H. B. (2003). The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Molecular pharmacology, 63(6), 1256–1272. https://doi.org/10.1124/mol.63.6.1256 Syed Haneef, S. A., & Ranganathan, S. (2019). Structural bioinformatics analysis of variants on GPCR function. Current opinion in structural biology, 55, 161–177. https://doi.org/10.1016/j.sbi.2019.04.007 Papasergi-Scott, M. M., Pérez-Hernández, G., Batebi, H., Gao, Y., Eskici, G., Seven, A. B., Panova, O., Hilger, D., Casiraghi, M., He, F., Maul, L., Gmeiner, P., Kobilka, B. K., Hildebrand, P. W., & Skiniotis, G. (2023). Time-resolved cryo-EM of G protein activation by a GPCR. bioRxiv : the preprint server for biology, 2023.03.20.533387. https://doi.org/10.1101/2023.03.20.533387

Greetings readers! We're excited to share our coverage of the latest developments in GPCRs for this week. In this edition, we have curated eight GPCR papers, five industry news, and two job ads. This week's highlight includes congrats to: David A Cooper, David Minh, et al., for their research on Intracellular pocket conformations, determine signaling through the μ opioid receptor. Dr. Minh and the team are looking for collaborators from academia and industry. Please reach out to him by email today! Dr. GPCR University Hurry! 3 out of the 25 spots have been filled! Team Registrations are also available! Early bird registration ends on April 18th. Join our upcoming Dr. GPCR University hands-on workshop with Dr. Samuel Hoare on Advanced data analysis for GPCR pharmacology, which will be held on Thursdays between May 9th and May 30th, 2024, from 10 am to 12 pm EDT. The workshop includes: Four x 2-hour Zoom sessions One-on-one meeting with Dr. Hoare Access to Dr. GPCR Ecosystem group Access to course materials and recordings Completion certificate One-year Dr. GPCR Ecosystem Premium Membership (restrictions apply) Early bird discount on future courses (restrictions apply) Save 25% with early bird registration until April 18th. We are pleased to announce five full scholarship opportunities for Dr. Hoare's workshop for individuals who live and work in developing countries. Please complete this form to take advantage of this opportunity. It's on a first-come, first-served basis. We also ask that you share this with your eligible colleagues. We define a developing country based on World Bank Classifications for its 2024 fiscal year. Dr. GPCR Symposia Join us on June 7th for our next symposium on Structural and Molecular Insights into GPCR Function. Stay updated for more details. Do you want to re-watch our recorded events? As a premium member, access on-demand content from past Dr. GPCR Symposiums and much more! If you have any research you would like to showcase to our community, you can submit a poster presentation. It doesn’t have to be a complete poster, just a few slides to spark the conversation. This is an excellent opportunity to network and increase your visibility on our platform. To begin, please fill out this form! If you've participated in our symposiums, please take a few minutes to complete this survey. Your feedback is valuable to us. Dr. GPCR Partnered Events April 22 - 23, 2024 | Endocrine Metabolic GPCRs Join the Endocrine Metabolic GPCRs event in Birmingham, UK, on April 22-23, 2024. Let’s dive into the Classified GPCR News from April 1st to 7th, 2024 GPCR Activation and Signaling GPRASP1 loss-of-function links to arteriovenous malformations by endothelial activating GPR4 signals Mechano-sensitivity of β2-adrenoceptors enhances constitutive activation of cAMP generation that is inhibited by inverse agonists OCaR1 endows exocytic vesicles with autoregulatory competence by preventing uncontrolled Ca2+ release, exocytosis, and pancreatic tissue damage Intracellular pocket conformations determine signaling through the μ opioid receptor GPCR Binders, Drugs, and more Predicting associations between drugs and G protein-coupled receptors using a multi-graph convolutional network GPCRs in Cardiology, Endocrinology, and Taste Dissecting a Brake for Airway Smooth Muscle Cell Movement Hepatic extracellular ATP/adenosine dynamics in zebrafish models of alcoholic and metabolic steatotic liver disease GPCRs in Oncology and Immunology Chemoattractant receptor signaling in humoral immunity Industry News Neurosterix launches with $63M to Advance Allosteric Modulator Therapeutics for Neurological Disorders Aelis Farma Reports Its 2023 Annual Financial Resultsand Confirms Its 2024 Outlook Sosei Heptares officially changed their name to Nxera Domain Therapeutics to participate at premier investor and healthcare conferences Montana Molecular is joining the BioTools Innovator program GPCR Events, Meetings, and Webinars May 13 - 17, 2024 | 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 7, 2024 | Chemotactic Cytokines June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein Mediated Signaling Networks June 25 - 29, 2024 | FENS Forum 2024 October 2024 | Biologics US 2024 October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs Senior Associate Scientist - Global Research Technologies Novo Nordisk Scientist I - Global Research Technologies Novo Nordisk Postdoctoral Associate Research Technologist I Senior Scientist- Internal Medicine Research Unit Postdoctoral Scholar – Synaptic physiology, optical imaging, substance use disorder, pharmacology Research Fellow Postdoctoral Fellow – Molecular Pharmacology of Feeding Behavior Join Dr. GPCR Ecosystem

Hello readers! Check out our GPCR coverage for this week. We have 17 GPCR papers and eight industry news. This week's highlight includes congrats to: Junyi Liang, Niña Caculitan, and Adam W Smith for their research on β2-adrenergic receptor associates with CXCR4 multimers in human cancer cells Dr. GPCR University Get ready for our next Dr. GPCR University hands-on workshop with Dr. Samuel Hoare on Advanced data analysis for GPCR pharmacology, which will be held on Thursdays between May 9th and May 30th, 2024, from 10 am to 12 pm EDT. The workshop includes: 4x 2 hours live Zoom sessions (45-50 minutes lecture + 1-hour Q&A) Thirty minutes one-on-one meetings with Dr. Hoare, according to his availability Access to the cohort’s Dr. GPCR Ecosystem group, where you can find Dr. Hoare and your classmates Access to the course materials and recordings once the course is completed Course completion certificate signed by Dr. Hoare and Dr. GPCR Complementary one-year Dr. GPCR Ecosystem Premium Membership ($250 value savings) - Only applicable to individual registrations Access to all content and all Dr. GPCR Ecosystem perks, including our forums, private groups, and all Ecosystem members Extended early bird discounts on future Dr.GPCR University courses in the next 12 months -  Only applicable to individual registrations This course will take a practical approach to Dr. Terry Kenakin’s Applying Pharmacology to Drug Discovery course. Continue to increase your knowledge of Pharmacology by joining this practical approach class today. Take advantage of the early bird registration until April 18th, 2024, to save 25%! Reserve your spot today. We are pleased to announce five full scholarship opportunities for Dr. Hoare's workshop for individuals who live and work in developing countries. Please complete this form to take advantage of this opportunity. We also ask that you share this with your eligible colleagues. Dr. GPCR Symposia With a premium membership, you can watch on-demand the Dr. GPCR Symposium on GPCR activation and signaling sessions. Our next symposium on Structural and Molecular Insights into GPCR Function is scheduled for June 7th. Stay tuned for more updates. If you want to showcase your research, you can submit a poster presentation to our community, take advantage of networking opportunities, and raise your profile on our platform. Get started by filling out this form! If you have a few minutes to spare and have participated in our symposiums, we would appreciate it if you could complete this survey. Your opinion is valuable to us. Dr. GPCR Partnered Events April 22 - 23, 2024 | Endocrine Metabolic GPCRs Join the Endocrine Metabolic GPCRs event in Birmingham, UK, on April 22-23, 2024. Let’s dive into the Classified GPCR News from March 25th to March 31st, 2024 GPCR Activation and Signaling PACAP key interactions with PAC1, VPAC1, and VPAC2 identified by molecular dynamics simulations Preassembly of specific Gβγ subunits at GABAB receptors through auxiliary KCTD proteins accelerates channel gating TRPM5 activation depends on a synergistic effect of calcium and PKC phosphorylation After wounding, a G-protein coupled receptor promotes the restoration of tension in epithelial cells Profiling the proximal proteome of the activated μ-opioid receptor Computational modelling of dynamic cAMP responses to GPCR agonists for exploration of GLP-1R ligand effects in pancreatic β-cells and neurons GPCR Binders, Drugs, and more In silico identification of a biarylamine acting as agonist at human β3 adrenoceptors and exerting BRL37344-like effects on mouse metabolism Mechanistic insights into sodium ion-mediated ligand binding affinity and modulation of 5-HT2B GPCR activity: implications for drug discovery and development GPCRs in Neuroscience Scutellaria baicalensis Georgi stems and leaves flavonoids promote neuroregeneration and ameliorate memory loss in rats through cAMP-PKA-CREB signaling pathway based on network pharmacology and bioinformatics analysis Unveiling the therapeutic prospects of EGFR inhibition in rotenone-mediated parkinsonism in rats: Modulation of dopamine D3 receptor Satellite glial GPR37L1 and its ligand maresin 1 regulate potassium channel signaling and pain homeostasis GPCRs in Oncology and Immunology The β2-adrenergic receptor associates with CXCR4 multimers in human cancer cells [Inhibitory effect of downregulating G protein-coupled receptor class C group 5 member A expression on lipopolysaccharide-induced inflammatory response in human gingival fibroblasts] Methods & Updates in GPCR Research Highly efficient GPCR immobilization with enhanced fouling resistance, salt tolerance, and chromatographic performance Fluorine-19 labeling of the tryptophan residues in the G protein-coupled receptor NK1R using the 5-fluoroindole precursor in Pichia pastoris expression Monitoring norepinephrine release in vivo using next-generation GRABNE sensors Reviews, GPCRs, and more Advances in GPCRs: Structure, Mechanisms, Disease, and Pharmacology Industry News Monash University pharmaceutical scientists honoured in NHMRC Research Excellence Awards Domain Therapeutics to Present Latest Data on DT-9045, a First-in-class Negative Allosteric Modulator of PAR2 for Immuno-oncology Crinetics Pharmaceuticals gets grant for patent granted for somatostatin modulators for treating hormone-related conditions Sosei Heptares Confirms Re-election of its Board and Executive Management Team and the Approval of Change of Company Name to Nxera Pharma Neurocrine Biosciences Announces Initiation of Phase 1 Clinical Study Evaluating Effects of NBI-1065890, a Second-Generation VMAT2 Inhibitor, in Healthy Adults Confo Therapeutics Secures VLAIO Grant Supporting Drug Discovery & Development In Endocrine And Metabolic Diseases How biotech companies are using AI to design drugs GPCR Therapeutics Announces Publication in PNAS Using Cutting Edge Spectroscopy to Detect GPCR Heteromers on Live Cancer Cells GPCR Events, Meetings, and Webinars April 1 - 4, 2024 | 19th Annual Drug Discovery Chemistry April 4 - 7, 2024 | American Physiology Summit April 5 - 10, 2024 | AACR Annual Meeting May 13 - 17, 2024 | 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 7, 2024 | Chemotactic Cytokines June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein Mediated Signaling Networks June 25 - 29, 2024 | FENS Forum 2024 October 2024 | Biologics US 2024 October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs Postdoctoral Associate Research Technologist I Senior Scientist- Internal Medicine Research Unit Postdoctoral Scholar – Synaptic physiology, optical imaging, substance use disorder, pharmacology Research Fellow Postdoctoral Fellow – Molecular Pharmacology of Feeding Behavior Director of Laboratory Operations - Single-molecule Imaging Center Scientific Assistant Join Dr. GPCR Ecosystem

GPCR activation typically occurs through the binding of agonists which stabilize receptor conformations that recruit and ultimately activate intracellular transducers. GPCRs are present in a range of conformations, and the binding of a ligand, as well as interactions with signaling molecules like G proteins, can selectively stabilize specific conformations (Gether 2000). In terms of pharmacology, GPCRs have been identified to exist in at least two distinct states: an active state characterized by high affinity for agonists when coupled to G proteins, and an inactive state in which their affinity for agonists diminishes in the absence of G proteins (Gether 2000), with numerous intermediate sub-states in between (Vauquelin and Van Liefde 2005; Yao et al. 2009). However, GPCRs are not simple on-off switches (Rosenbaum, Rasmussen, and Kobilka 2009), since they are able to adopt an active conformation without agonist engagement referred to as receptor constitutive or basal activity. The initial demonstration of spontaneous or "constitutive" receptor activity was reported for the β2-adrenergic receptor in 1984 (Cerione et al. 1984), where reconstitution of purified β2-adrenergic receptors from guinea pig lung in conjunction with purified Gαs from human erythrocytes led to an elevation in GTPase activity of Gαs without the presence of a ligand. Subsequently, opioid receptors were shown to constitutively activate Gi proteins in a membrane preparation without the need for an agonist (Costa and Herz 1989). GPCR ligands pharmacology The impact of a ligand on a receptor's structure and biophysical attributes, and consequently on the biological response, is referred to as ligand efficacy. Natural and synthetic ligands can be categorized into four distinct efficacy classes: 1) full agonists produce the maximal response and can differ in intrinsic efficacy; 2) partial agonists are incapable of inducing maximal activity even when they are present at saturating concentrations; 3) neutral antagonists have null intrinsic efficacy, thus not affecting receptor signaling activity, and can compete with agonist ligands; 4) and inverse agonists decrease the level of receptor constitutive activity. In the same way that agonists possess intrinsic efficacy, inverse agonists also exhibit varying degrees of negative intrinsic efficacy, leading to the presence of both robust and less potent (partial) inverse agonism (Rosenbaum, Rasmussen, and Kobilka 2009). GPCR targeting drugs: orthosteric vs allosteric sites Most of the drugs targeting GPCRs bind to the orthosteric site of the receptor, eliciting various effects, such as receptor activation (e.g., agonists or partial agonists), inhibition of activation (e.g., antagonists), or produce an inversion of the functional response (e.g., inverse agonists). Despite the existence of numerous drugs designed for this primary binding site, there are significant challenges in creating ligands that are both safe and effective. Those include the risk of unintended off-target effects, limited selectivity due to closely related receptor binding sites, the inability to target large and diffuse binding sites activated by peptides or proteins, and the disruption of natural spatial and temporal signaling patterns regulated by physiological systems (Wold and Zhou 2018). An alternative and promising approach is allosteric modulation. Allosteric binding sites on the receptor are those topographically distinct from (do not exhibit any overlap with) the orthosteric site (Rosenbaum, Rasmussen, and Kobilka 2009). Over the past decade, there has been a notable growth in the discovery of allosteric modulators for GPCRs which possess the capability to modulate and fine-tune the affinity and/or efficacy of orthosteric ligands. While this has the potential to enhance GPCR subtype-selectivity, it also presents a significant challenge when it comes to detecting and confirming allosteric behaviors (Keov, Sexton, and Christopoulos 2011). Compounds employing an allosteric mechanism of action can theoretically offer several advantages compared to orthosteric ligands when considered as potential therapeutic agents. Allosteric modulators that do not exhibit agonistic properties remain inactive in the absence of endogenous orthosteric activity, therefore having the potential to maintain the temporal and spatial aspects of natural physiological signaling. The significance of spatio-temporal attributes in signaling is demonstrated in processes like neurotransmission and chemokine signaling, extending to numerous other GPCR-regulated systems such as free fatty acid receptors (FFARs), now regarded as targets for therapeutic intervention for metabolic diseases such as liver disease, obesity and diabetes (Secor et al. 2021; Wold and Zhou 2018). Moreover, they have the potential to enhance target selectivity, which can arise from greater sequence variation in allosteric sites among receptor subtypes when compared to the conserved orthosteric region, or from selective cooperativity with a particular subtype while excluding others (Christopoulos 2002; Lazareno et al. 2004). This is particularly important when dealing with receptor subtypes that exhibit significant similarity in their orthosteric binding sites, such as chemokine receptors. On the other hand, selectivity could be achieved by merging both orthosteric and allosteric pharmacophores within a single compound, resulting in a novel category of GPCR ligands referred to as 'bitopic' (Valant et al. 2008). A third advantage is that they offer the prospect of reducing the risk of overdose, given that their activity is dependent on the concentration of the orthosteric ligand. In this context, allosteric modulators exhibiting constrained positive or negative cooperativity are characterized by having an upper limit on the extent of their allosteric influence, an attribute that offers a considerable degree of adjustability in terms of pharmacological effects, allowing for the administration of substantial doses of allosteric modulators with a diminished risk of target-related toxicity (Wold et al. 2018). GPCRs functional selectivity Recent research has revealed a more intricate understanding of GPCR behavior, extending beyond the traditional G-protein and second messenger activation pathways. Agonist binding to GPCRs doesn't always trigger all associated events sequentially. Depending on the specific functional outcome measured (e.g. activation, interaction with accessory proteins, dimerization, phosphorylation, internalization, or desensitization), the same drug acting on the same receptor in the same cellular context can produce a range of effects, from full activation to partial activation to inverse agonism. This variability in drug effects is due to different ligands inducing unique GPCR conformations that selectively activate specific cellular outcomes linked to that GPCR. This phenomenon is termed "stimulus-trafficking," "biased agonism," or "functional selectivity" (Urban et al. 2007). Overall, GPCRs are intriguing molecules that deviate from typical textbook proteins. They do not have a binary active or inactive state but instead can adopt numerous distinct conformational states, each of which triggers a distinct array of physiological effects. They can be compared to molecular rheostats, capable of sampling a spectrum of conformations with relatively small energy differences (Ma, Lee, and Vaidehi 2020). The ligand alters the balance of these conformations, increasing the prevalence of some infrequent ones, preventing access to others, or allowing previously inaccessible conformations. To understand how ligands or drugs affect GPCRs is crucial to grasp the dynamics of these conformational shifts and identify the most relevant forms.

Hello readers! BIG NEWS! Check out our GPCR coverage for this week. We have 15 GPCR papers and four industry news. This week's highlight includes congrats to: Drs. Miles Thompson, Alexander Hauser, Caroline Gorvin et al. for their research on GPCR gene variants and human genetic disease. Dr. GPCR Symposia With a premium membership, you can watch on-demand the Dr. GPCR Symposium on GPCR activation and signaling sessions. Our next symposium on Structural and Molecular Insights into GPCR Function. is scheduled for June 7th. Stay tuned for more updates. If you want to showcase your research, you can submit a poster presentation to our community, take advantage of networking opportunities, and raise your profile on our platform. Get started by filling out this form! If you have a few minutes to spare and have participated in our symposiums, we would appreciate it if you could complete this survey. Your opinion is valuable to us. Dr. GPCR Partnered Events April 22 - 23, 2024 | Endocrine Metabolic GPCRs Join the Endocrine Metabolic GPCRs event in Birmingham, UK, on April 22-23, 2024. Let’s dive into the Classified GPCR News from March 18th to 24th, 2024 GPCR Activation and Signaling Calcium-Driven In Silico Inactivation of a Human Olfactory Receptor Deciphering the role of glycosaminoglycans in GPCR signaling G protein-coupled receptor-mediated autophagy in health and disease GPCR Binders, Drugs, and more Elucidation of active components and target mechanism in Jinqiancao granules for the treatment of prostatitis and benign prostatic hyperplasia GPCRs in Cardiology, Endocrinology, and Taste Blockade of endothelial adenosine receptor 2A suppresses atherosclerosis in vivo through inhibiting CREB-ALK5-mediated endothelial to mesenchymal transition Role of pH-sensing receptors in colitis GPCRs in Oncology and Immunology Polarizing itch Biochemical pharmacology of adenylyl cyclases in cancer Methods & Updates in GPCR Research A multicolor suite for deciphering population coding of calcium and cAMP in vivo Cryo-EM advances in GPCR structure determination Visualization of endogenous G proteins on endosomes and other organelles Reviews, GPCRs, and more G protein-coupled receptor (GPCR) gene variants and human genetic disease Advances and challenges in cancer immunoprevention and immune interception Structural and Molecular Insights into GPCR Function Structural bioinformatics studies of serotonin, dopamine and norepinephrine transporters and their AlphaFold2 predicted water-soluble QTY variants and uncovering the natural mutations of L->Q, I->T, F->Y and Q->L, T->I and Y->F Industry News Sosei Heptares Doses First Subject in Phase 1 Trial with HTL0033744, an EP4 Agonist for Inflammatory Bowel Disease (IBD) Domain Therapeutics and Chime Biologics Form Manufacturing Pact for Antibody Cancer Immunotherapy Sosei Heptares Regains Full Ownership from GSK of HTL0027477, a Clinic-ready, First-in-Class Oral GPR35 Agonist for Inflammatory Bowel Disease Crinetics’ Once-Daily Oral Paltusotine Achieved The Primary And All Secondary Endpoints In The Phase 3 Pathfndr-2 Study In Acromegaly Patients GPCR Events, Meetings, and Webinars March 24 - 29, 2024 | Ligand Recognition and Molecular Gating Conference April 1 - 4, 2024 | 19th Annual Drug Discovery Chemistry April 4 - 7, 2024 | American Physiology Summit April 5 - 10, 2024 | AACR Annual Meeting May 13 - 17, 2024 | 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 7, 2024 | Chemotactic Cytokines June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein Mediated Signaling Networks June 25 - 29, 2024 | FENS Forum 2024 October 2024 | Biologics US 2024 October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs Postdoctoral Associate Research Technologist I Senior Scientist- Internal Medicine Research Unit Postdoctoral Scholar – Synaptic physiology, optical imaging, substance use disorder, pharmacology Research Fellow Postdoctoral Fellow – Molecular Pharmacology of Feeding Behavior Director of Laboratory Operations - Single-molecule Imaging Center Scientific Assistant Join Dr. GPCR Ecosystem

Hello readers! We had an amazing week. Don’t miss out on our GPCR coverage for this week. We have 10 GPCR papers, five industry news, and one job ad. This week's highlight includes congrats to: Makaía M Papasergi-Scott, Peter Gmeiner, Brian K Kobilka, Georgios Skiniotis, et al. for their research on Time-resolved cryo-EM of G-protein activation by a GPCR Remi Janicot, Alex Luebbers, Mikel Garcia-Marcos, et al. for their work on Direct interrogation of context-dependent GPCR activity with a universal biosensor platform Dr. GPCR Symposia We extend our heartfelt thanks to all speakers and participants for making our recent Dr. GPCR Symposium on GPCR activation and signaling a resounding success! If you missed it, don't worry – you can catch the sessions on-demand with a premium membership. Exciting news awaits! We're gearing up for our next symposium on June 7th, focusing on Structural and Molecular Insights into GPCR Function. Stay tuned for more information coming soon. Interested in showcasing your research? Submit a poster presentation to our community, seize networking opportunities, and elevate your profile on our platform. Simply fill out this form to get started! Are you free for a few minutes? If you participated in our symposiums, please take a moment to complete this survey. Your opinion is valuable to us. Dr. GPCR University Save the date for our upcoming workshop, starting May 9th, 2024, featuring Dr. Sam Hoare as our instructor. Under Dr. Hoare's expert guidance, you will gain invaluable skills in data analysis. More details are coming soon—stay tuned! Dr. Terry Kenakin's "Applying Pharmacology to Drug Discovery" course at Dr. GPCR University was tremendously successful. If you're eager to attend, join our waitlist for updates on its return later this year. Those on the waitlist will be notified first of the course dates, so hurry. Dr. GPCR Partnered Events April 22 - 23, 2024 | Endocrine Metabolic GPCRs Join the Endocrine Metabolic GPCRs event in Birmingham, UK, on April 22-23, 2024. Let’s dive into the Classified GPCR News from March 11th to 17th, 2024 Adhesion GPCRs ADGRG1, an adhesion G protein-coupled receptor, forms oligomers GPCR Activation and Signaling Unraveling the crosstalk between renin-angiotensin system receptors Arrestin-centred interactions at the membrane and their conformational determinants The polybasic region in Gαi proteins: Relevant or not? Insights from Gαi3 research GPCRs in Cardiology, Endocrinology, and Taste The Prostaglandin E2 EP3 Receptor Has Disparate Effects on Islet Insulin Secretion and Content in β-cells in a High Fat Diet-induced Mouse Model of Obesity GPCRs in Neuroscience Xanthurenic acid: A role in brain intercellular signaling Are there sex differences in oxytocin and vasopressin V1a receptors ligand binding affinities? Methods & Updates in GPCR Research Direct interrogation of context-dependent GPCR activity with a universal biosensor platform Protocol to visualize and quantify the COPII concentration and anterograde transport of nascent G protein-coupled receptors Structural and Molecular Insights into GPCR Function Time-resolved cryo-EM of G-protein activation by a GPCR Industry News Domain Therapeutics and Chime Biologics announce manufacturing agreement  to advance novel anti-CCR8 antibody  for cancer immunotherapy Novo Holdings Portfolio Company Amolyt Pharma Enters into Definitive Agreement to be Acquired by AstraZeneca Basecamp Research Launches BaseFold: A Breakthrough in 3D Protein Structure Prediction of Large, Complex Protein Structures Newly discovered adhesion GPCR mayo controls midgut development in Drosophila Karuna Therapeutics announces that is now part of Bristol Myers Squibb GPCR Events, Meetings, and Webinars March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition and Molecular Gating Conference April 1 - 4, 2024 | 19th Annual Drug Discovery Chemistry April 4 - 7, 2024 | American Physiology Summit April 5 - 10, 2024 | AACR Annual Meeting May 13 - 17, 2024 | 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 7, 2024 | Chemotactic Cytokines June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein Mediated Signaling Networks June 25 - 29, 2024 | FENS Forum 2024 October 2024 | Biologics US 2024 October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs NEW Postdoctoral Associate Research Technologist I Senior Scientist- Internal Medicine Research Unit Postdoctoral Scholar – Synaptic physiology, optical imaging, substance use disorder, pharmacology Research Fellow Postdoctoral Fellow – Molecular Pharmacology of Feeding Behavior Director of Laboratory Operations - Single-molecule Imaging Center Scientific Assistant Join Dr. GPCR Ecosystem

Hi readers! Get the latest updates on breakthroughs in GPCR research with our concise and comprehensive summaries. Stay ahead of the curve! This week's highlight includes congrats to Drs. Khaled Abd-Elrahman, Stephen Ferguson et al. Their research reveals how VU0486846 reduces neurogliosis in female Alzheimer's mice. Dr. GPCR Symposia TOMORROW, we are hosting a symposium on GPCR activation and signaling. We are pleased to confirm the participation of a great lineup of speakers, namely Drs. Franziska Heydenreich, Sudarshan Rajagopal, Graham Ladds, Cesare Orlandi, Simone Prömel and Michel Bouvier. Additionally, we are having a Panel Discussion on Publishing in Academia with Drs. Stuart Maudsley, Nicole Perry-Hauser, Lauren Slosky, Cesare Orlandi, and Simone Prömel. Please note that we moved our clocks ahead in North America. If you are joining from anywhere else in the world, please plan accordingly. Don't miss out, and mark your calendar! Dr. GPCR University Save the date for our upcoming workshop starting May 9th, 2024, featuring Dr. Sam Hoare as our instructor. Gain invaluable skills in data analysis under Dr. Hoare's expert guidance. More details are coming soon—stay tuned! Dr. Terry Kenakin's "Applying Pharmacology to Drug Discovery" course at Dr. GPCR University was tremendously successful. If you're eager to attend, join our waitlist for updates on its return later this year. Those on the waitlist will be the first notified of the course dates, so hurry. Dr. GPCR Partnered Events April 22 - 23, 2024 | Endocrine Metabolic GPCRs Join the Endocrine Metabolic GPCRs event in Birmingham, UK, on April 22-23, 2024. Let’s dive into the Classified GPCR News from March 4th to 10th, 2024 GPCR Activation and Signaling Glu1022.53-Mediated Early Conformational Changes in the Process of Light-Induced Green Cone Pigment Activation Molecular dynamics-based identification of binding pathways and two distinct high-affinity sites for succinate in succinate receptor 1/GPR91 Specific pharmacological and Gi/o protein responses of some native GPCRs in neurons Beyond the Nucleus: Plastic Chemicals Activate G Protein-Coupled Receptors GPCRs in Neuroscience A M1 muscarinic acetylcholine receptor-specific positive allosteric modulator VU0486846 reduces neurogliosis in female Alzheimer's mice The association of GNB5 with Alzheimer disease revealed by genomic analysis restricted to variants impacting gene function Interaction modes of human orexin 2 receptor with selective and nonselective antagonists studied by NMR spectroscopy Up-regulation of GPR139 in the medial septum ameliorates cognitive impairment in two mouse models of Alzheimer's disease GPCRs in Oncology and Immunology Itaconate in host inflammation and defense Methods & Updates in GPCR Research Improved green and red GRAB sensors for monitoring spatiotemporal serotonin release in vivo Reviews, GPCRs, and more 2023 Julius Axelrod Symposium: Plant-derived molecules acting on GPCRs Molecular characterization of recombinant LSDV isolates from 2022 outbreak in Indonesia through phylogenetic networks and whole-genome SNP-based analysis Industry News Boehringer Ingelheim and Sosei Heptares join forces to develop first-in-class treatments targeting all symptoms of schizophrenia Sosei Heptares to receive US$2.5 million milestone payment from Formosa Pharmaceuticals Are GLP-1s finding the right balance in obesity? Deciphering the role of GPCRs in obesity pathology for drug development GPCR Events, Meetings, and Webinars March 13 - 15 | Biologics 2024 March 13 - 15 | 9th German Pharm-Tox Summit March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition and Molecular Gating Conference April 1 - 4, 2024 | 19th Annual Drug Discovery Chemistry April 4 - 7, 2024 | American Physiology Summit April 5 - 10, 2024 | AACR Annual Meeting May 13 - 17, 2024 | 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 7, 2024 | Chemotactic Cytokines June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein Mediated Signaling Networks June 25 - 29, 2024 | FENS Forum 2024 October 2024 | Biologics US 2024 October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs NEW Research Technologist I Senior Scientist- Internal Medicine Research Unit Postdoctoral Scholar – Synaptic physiology, optical imaging, substance use disorder, pharmacology Research Fellow Postdoctoral Fellow – Molecular Pharmacology of Feeding Behavior Director of Laboratory Operations - Single-molecule Imaging Center Scientific Assistant Postdoctoral Fellowship- Mechanistic Biology Join Dr. GPCR Ecosystem

Welcome to our weekly GPCR Newsletter - your source for the latest insights, breakthroughs, and updates! This week's highlight includes congrats to: Christina Katharina Kuhn, Drs. Sandra Berndt, Ines Liebscher, and Susanne Horn et. al for their for their research on adhesion GPCR transcript variants from publicly available human samples. Howard Rockman, and Dr. Robert Lefkowitz for their work on GPCRs: from radioligand binding to cellular signaling Dr. GPCR Symposia Mark your calendars! Next week, on March 15th, we are hosting a symposium on GPCR activation and signaling. We are delighted to confirm the participation of esteemed speakers such as Drs. Franziska Heydenreich, Sudarshan Rajagopal, Graham Ladds, Cesare Orlandi, Simone Prömel and Michel Bouvier. Additionally, we will be hosting a poster session in Zoom breakout rooms. If you want to share your work with our community, please don’t hesitate to fill out this form. We also value your feedback. If you attended our 2023 Symposia, please take a moment to complete this survey. Dr. GPCR University Great News! The Dr. GPCR University Course, ‘Applying Pharmacology to Drug Discovery,’ led by Dr. Terry Kenakin, was a resounding success; we have a waitlist for those eager to attend this course, which wil be coming back later this year. Mark your calendar; we’re planning a workshop for May 2024 with Dr. Sam Hoare as our instructor. With Dr. Hoare, you’ll learn how to analyze your data like a pro. Stay tuned for more information. Dr. GPCR Partnered Events April 22 - 23, 2024 | Endocrine Metabolic GPCRs Join the Endocrine Metabolic GPCRs event in Birmingham, UK, on April 22-23, 2024. Let’s dive into the Classified GPCR News from February 26th to March 3rd, 2024 Adhesion GPCRs The repertoire and structure of adhesion GPCR transcript variants assembled from publicly available deep-sequenced human samples GPCR Activation and Signaling Structure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution G protein-coupled receptors: from radioligand binding to cellular signaling GPR101: Modeling a constitutively active receptor linked to X-linked acrogigantism State-dependent dynamics of extramembrane domains in the β2 -adrenergic receptor β-Arrestin-independent endosomal cAMP signaling by a polypeptide hormone GPCR Bias translation: The final frontier? Bicarbonate signalling via G protein-coupled receptor regulates ischaemia-reperfusion injury GPCRs in Cardiology, Endocrinology, and Taste RGS4 controls airway hyperresponsiveness through GAP-independent mechanisms Phenylacetyl glutamine (PAGln) enhances cardiomyocyte death after myocardial infarction through β1 adrenergic receptor GPCRs in Neuroscience Discovery of potential TAAR1 agonist targeting neurological and psychiatric disorders: An in silico approach Opioid modulation of prefrontal cortex cells and circuits GPCRs in Oncology and Immunology RGS20 promotes non-small cell lung carcinoma proliferation via autophagy activation and inhibition of the PKA-Hippo signaling pathway Blockade of vasoactive intestinal peptide receptor 2 (VIPR2) signaling suppresses cyclin D1-dependent cell-cycle progression in MCF-7 cells Methods & Updates in GPCR Research Cryo-electron microscopy for GPCR research and drug discovery in endocrinology and metabolism Reviews, GPCRs, and more Butyrate as a promising therapeutic target in cancer: From pathogenesis to clinic (Review) Will the hype of automated drug discovery finally be realized? Commentary: Analyzing invertebrate bitopic cadherin G protein-coupled receptors that bind cry toxins of Bacillus thuringiensis Industry News Domain Therapeutics announces the promotion of Stephan Schann to the role of Chief Scientific Officer Crinetics Reports Fourth Quarter And Full Year 2023 Financial Results And Provides Corporate Update. Biagon Officially Incorporated In The State Of Illinois Septerna divulges new TSHR antagonists for hyperthyroidism Unlocking the Secrets of Cellular Communication: The Revolutionary Impact of Cryo-EM on GPCR Research GPCR Events, Meetings, and Webinars March 13 - 15 | Biologics 2024 March 13 - 15 | 9th German Pharm-Tox Summit March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition and Molecular Gating Conference April 1 - 4, 2024 | 19th Annual Drug Discovery Chemistry April 4 - 7, 2024 | American Physiology Summit April 5 - 10, 2024 | AACR Annual Meeting May 13 - 17, 2024 | 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 7, 2024 | Chemotactic Cytokines June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein Mediated Signaling Networks June 25 - 29, 2024 | FENS Forum 2024 October 2024 | Biologics US 2024 October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs Senior Scientist- Internal Medicine Research Unit Postdoctoral Scholar – Synaptic physiology, optical imaging, substance use disorder, pharmacology Research Fellow Postdoctoral Fellow – Molecular Pharmacology of Feeding Behavior Director of Laboratory Operations - Single-molecule Imaging Center Scientific Assistant Postdoctoral Fellowship- Mechanistic Biology Research Scientist Join Dr. GPCR Ecosystem

When it comes to signal transduction, cellular context matters. The cellular context is crucial for understanding the diverse signaling outcomes mediated by different receptors including G protein coupled receptors (GPCRs). The localization of GPCRs to specific intracellular compartments dictates the spatial and temporal dynamics of signaling, ultimately shaping cellular responses1. For example, the lipid composition of intracellular membranes may influence GPCR dynamics and signaling outcomes, changing the receptor conformation and accessibility to ligands2. Traditionally, GPCR signaling was believed to primarily occur at the plasma membrane. However, emerging evidence suggests that GPCRs also signal from intracellular membranes including endosomes, the Golgi apparatus, and the nuclear membrane, leading to spatially biased signaling responses. In the endosomes, sustained G protein signaling has been associated with prolonged interactions between GPCRs, G proteins, and arrestins on endosomal membranes3,4. This phenomenon has been demonstrated for receptors such as the parathyroid hormone receptor (PTHR) and the vasopressin receptor 2 (V2R). The formation of stable complexes between GPCRs and signaling effectors on endosomes supports multiple rounds of G protein activation, leading to sustained cellular responses5,6. The role of β-arrestins in endosomal signaling has been extensively studied, highlighting their ability to scaffold various kinases and modulate downstream signaling pathways. Showing that this spatially biased signaling through arrestins can influence transcriptional responses and contribute to physiological processes such as meiosis in ovarian follicles and pain neurotransmission7,1. In addition to endosomal signaling, GPCRs are also known to localize to the Golgi apparatus, where they can be activated by ligands and initiate signaling cascades. The Golgi-localized signaling of GPCRs such as the β1-adrenergic receptor (B1AR) and the thyroid-stimulating hormone receptor (TSHR) has been shown to regulate distinct cellular processes, including phospholipase C epsilon (PLCε)-dependent signaling and transcriptional responses mediated by CREB phosphorylation1,8,9. Furthermore, GPCRs localized to the nuclear membrane have emerged as important regulators of gene transcription and cellular responses. Activation of nuclear GPCRs, such as the metabotropic glutamate receptor 5 (mGluR5), can lead to sustained calcium signaling and activation of transcription factors like CREB and Elk1, influencing synaptic plasticity and neuronal function10. GPCRs have also been identified within the mitochondria. Initial investigations revealed the positioning of the cannabinoid CB1 receptor on the outer mitochondrial membrane of skeletal and myocardial cells, where stimulation of mitochondrial CB1 receptors by lipophilic agonists in these tissues was associated with the modulation of oxidative activity via enzymes involved in pyruvate metabolism11. As the mechanisms underlying spatial bias in GPCR signaling involve both temporal and spatial components, sustained signaling responses from intracellular compartments can be regulated by the kinetics of signaling and the spatial organization of signaling effectors, including G proteins, adenylyl cyclases, and kinases. Therefore the presence of membrane microdomains and protein scaffolds, further contributes to the spatial regulation of GPCR signaling and downstream responses1,2. The clinical relevance of understanding these signaling mechanism is linked with the fact that dysregulation of compartmentalized GPCR signaling has been implicated in various diseases. For instance, aberrant endosomal signaling by GPCRs has been linked to disorders such as cancer, neurodegenerative diseases, and cardiovascular disorders. Therefore, targeting specific intracellular compartments and signaling pathways associated with GPCRs holds promise for the development of novel therapeutic interventions12. Tagging GPCRs expressed in cellular compartments such as the nucleus or endosomes presents several pharmaceutical challenges for many reasons. These compartments have distinct biochemical environments, which may affect the stability and functionality of the tagging molecules. For example, the nuclear envelope presents a barrier that restricts the passage of large molecules, making it challenging to deliver tagging agents effectively. Additionally, the conditions within endosomes, such as low pH and high protease activity, can degrade tagging molecules, reducing their effectiveness1,8,12. Furthermore, targeting GPCRs in specific cellular compartments requires precise delivery mechanisms to ensure the tagging molecules reach their intended destination. This may involve the development of specialized delivery vehicles, such as nanoparticles or liposomes, capable of penetrating cellular membranes and delivering the tagging agents to the desired compartment. Another challenge is the potential interference of tagging molecules with GPCR function. Tagging molecules may alter the conformation or activity of GPCRs, leading to unintended effects on downstream signaling pathways. Therefore, it is essential to design tagging strategies that minimize interference with GPCR function while allowing for accurate detection and localization. Overall, the pharmaceutical challenges associated with tagging GPCRs expressed in cellular compartments require innovative approaches to overcome barriers related to stability, delivery, interference with GPCR function, and off-target effects. References Crilly, S. E., & Puthenveedu, M. A. (2021). Compartmentalized GPCR Signaling from Intracellular Membranes. The Journal of membrane biology, 254(3), 259–271. https://doi.org/10.1007/s00232-020-00158-7 Gonçalves-Monteiro, S., Ribeiro-Oliveira, R., Vieira-Rocha, M. S., Vojtek, M., Sousa, J. B., & Diniz, C. (2021). Insights into Nuclear G-Protein-Coupled Receptors as Therapeutic Targets in Non-Communicable Diseases. Pharmaceuticals (Basel, Switzerland), 14(5), 439. https://doi.org/10.3390/ph14050439 Chen, K. E., Healy, M. D., & Collins, B. M. (2019). Towards a molecular understanding of endosomal trafficking by Retromer and Retriever. Traffic (Copenhagen, Denmark), 20(7), 465–478. https://doi.org/10.1111/tra.12649 Ribeiro-Oliveira, R., Vojtek, M., Gonçalves-Monteiro, S., Vieira-Rocha, M. S., Sousa, J. B., Gonçalves, J., & Diniz, C. (2019). Nuclear G-protein-coupled receptors as putative novel pharmacological targets. Drug discovery today, 24(11), 2192–2201. https://doi.org/10.1016/j.drudis.2019.09.003 Ferrandon, S., Feinstein, T. N., Castro, M., Wang, B., Bouley, R., Potts, J. T., Gardella, T. J., & Vilardaga, J. P. (2009). Sustained cyclic AMP production by parathyroid hormone receptor endocytosis. Nature chemical biology, 5(10), 734–742. https://doi.org/10.1038/nchembio.206 Wei, H., Ahn, S., Shenoy, S. K., Karnik, S. S., Hunyady, L., Luttrell, L. M., & Lefkowitz, R. J. (2003). Independent beta-arrestin 2 and G protein-mediated pathways for angiotensin II activation of extracellular signal-regulated kinases 1 and 2. Proceedings of the National Academy of Sciences of the United States of America, 100(19), 10782–10787. https://doi.org/10.1073/pnas.1834556100 Lyga, S., Volpe, S., Werthmann, R. C., Götz, K., Sungkaworn, T., Lohse, M. J., & Calebiro, D. (2016). Persistent cAMP Signaling by Internalized LH Receptors in Ovarian Follicles. Endocrinology, 157(4), 1613–1621. https://doi.org/10.1210/en.2015-1945 Irannejad, R., Pessino, V., Mika, D., Huang, B., Wedegaertner, P. B., Conti, M., & von Zastrow, M. (2017). Functional selectivity of GPCR-directed drug action through location bias. Nature chemical biology, 13(7), 799–806. https://doi.org/10.1038/nchembio.2389 Godbole, A., Lyga, S., Lohse, M. J., & Calebiro, D. (2017). Internalized TSH receptors en route to the TGN induce local Gs-protein signaling and gene transcription. Nature communications, 8(1), 443. https://doi.org/10.1038/s41467-017-00357-2 Jong, Y. I., & O'Malley, K. L. (2017). Mechanisms Associated with Activation of Intracellular Metabotropic Glutamate Receptor, mGluR5. Neurochemical research, 42(1), 166–172. https://doi.org/10.1007/s11064-016-2026-6 Mendizabal-Zubiaga, J., Melser, S., Bénard, G., Ramos, A., Reguero, L., Arrabal, S., Elezgarai, I., Gerrikagoitia, I., Suarez, J., Rodríguez De Fonseca, F., Puente, N., Marsicano, G., & Grandes, P. (2016). Cannabinoid CB1 Receptors Are Localized in Striated Muscle Mitochondria and Regulate Mitochondrial Respiration. Frontiers in physiology, 7, 476. https://doi.org/10.3389/fphys.2016.00476 Insel, P. A., Sriram, K., Wiley, S. Z., Wilderman, A., Katakia, T., McCann, T., Yokouchi, H., Zhang, L., Corriden, R., Liu, D., Feigin, M. E., French, R. P., Lowy, A. M., & Murray, F. (2018). GPCRomics: GPCR Expression in Cancer Cells and Tumors Identifies New, Potential Biomarkers and Therapeutic Targets. Frontiers in pharmacology, 9, 431. https://doi.org/10.3389/fphar.2018.00431

Hello readers! Check out our GPCR coverage for this week. We have 19 GPCR papers, six industry news, two events, and two job ads. This week's highlight includes congrats to: Johanna Lena Schön, and Dr. Simone Prömel et al. for their study on the effect of Flamingo (FMI-1) on body size and extracellular matrix. Isabella Russell, Drs. Patrick Sexton, and Matthew Belousoff et al. for their work on Lipid-Dependent Activation of the Orphan G Protein-Coupled Receptor GPR3 Dr. GPCR Symposia Mark your calendars! In just two weeks, on March 15th, we are hosting a symposium on GPCR activation and signaling. We are delighted to confirm the participation of esteemed speakers such as Drs. Franziska Heydenreich, Sudarshan Rajagopal, Graham Ladds, Cesare Orlandi, Simone Prömel and Michel Bouvier. Additionally, we will be conducting a poster session in Zoom breakout rooms. If you want to share your work with our community, please don’t hesitate to fill out this form. We also value your feedback. If you attended our 2023 Symposia, please take a moment to complete this survey. Dr. GPCR University Today marks the conclusion of the Dr.GPCR University course, ‘Applying Pharmacology to Drug Discovery,’ expertly led by Dr. Terry Kenakin. We would like to extend our heartfelt thanks to Dr. Kenakin for his invaluable contributions and to all the participants for their active involvement and enthusiasm. If you were interested in this course but missed the opportunity to register, fret not! You can still sign up for our waitlist. We will be offering this live course again later this year. By being on the waitlist, you’ll be the first to be notified when official registrations open for the next session. Dr. GPCR Volunteers Join our dynamic team as a volunteer! You'll share your contributor articles with the community, stay updated with GPCR literature, join a dynamic team, network with GPCR scientists at our events, and get a complimentary Premium Membership with only 4 hours/monthly commitment on your part. If you are interested in applying, please email us your CV/Resume at  Hello@DrGPCR.com. Dr. GPCR Partnered Events March 5 - 7, 2024 | 3rd GPCRs - Targeted Drug Discovery Summit. Join Dr. GPCR Founder Dr. Yamina Berchiche at the 3rd GPCRs Summit in Boston on March 5-7, 2024. Dr. GPCR Members get 10% off with code MPDRGPCR10. April 22 - 23, 2024 | Endocrine Metabolic GPCRs Join Dr. GPCR Founder Dr. Yamina Berchiche at the Endocrine Metabolic GPCRs event in Birmingham, UK, on April 22-23, 2024. Let’s dive into the Classified GPCR News from  February 19th to 25th, 2024 Adhesion GPCRs The Adhesion GPCR and PCP component Flamingo (FMI-1) alters body size and regulates the composition of the extracellular matrix GPCR Activation and Signaling Probing Activation and Conformational Dynamics of the Vesicle-Reconstituted β2 Adrenergic Receptor at the Single-Molecule Level Pharmacological characterization of seven human histamine H3 receptor isoforms Lipid-Dependent Activation of the Orphan G Protein-Coupled Receptor, GPR3 After wounding, a G-protein coupled receptor promotes the restoration of tension in epithelial cells GPCR Binders, Drugs, and more Advances in structure-based drug design: The potential for precision therapeutics in psychiatric disorders Discovery of a Photoaffinity Probe that Captures the Active Conformation of the Cannabinoid CB2 Receptor GPCRs in Neuroscience G protein-coupled receptor-based thermosensation determines temperature acclimatization of Caenorhabditis elegan Species-Specific Duplicated FMRFaR-like Gene A62 Regulates Spontaneous Locomotion in Apolygus lucorum Whole Brain Mapping of Orexin Receptor mRNA Expression Visualized by Branched In Situ Hybridization Chain Reaction Orphan GPR52 as an emerging neurotherapeutic target Sustained antidepressant effects of ketamine metabolite involve GABAergic inhibition-mediated molecular dynamics in aPVT glutamatergic neurons GPCRs in Oncology and Immunology TIPE proteins control directed migration of human T cells by directing GPCR and lipid second messenger signaling Methods & Updates in GPCR Research A bioluminescent and homogeneous assay for monitoring GPCR-mediated cAMP modulation and PDE activity GPCRs in the round: SMA-like copolymers and SMALPs as a platform for investigating GPCRs Reviews, GPCRs, and more Fragment-Based Design, Synthesis, and Characterization of Aminoisoindole-Derived Furin Inhibitors A Bright Future? A Perspective on Class C GPCR Based Genetically Encoded Biosensors Emergence of lumpy skin disease virus (LSDV) infection in domestic Himalayan yaks (Bos grunniens) in Himachal Pradesh, India Structural and Molecular Insights into GPCR Function Exploring Diverse Signaling Mechanisms of G Protein-Coupled Receptors through Structural Biology Industry News INV-347 by Inversago Pharma for Obesity: Likelihood of Approval Septerna to Participate in Upcoming Investor and Industry Conferences Sosei and IPJ to become Nxera Pharma from April Orion Biotechnology will be at the BIO CEO & Investor Conference Salipro Biotech AB will be at the Oxford Global’s Biologics event GPCR Events, Meetings, and Webinars February 20, 2024 | Career Opportunities in Pharmacology and Drug Discovery NEW March 13 - 15 | Biologics 2024 March 13 - 15 | 9th German Pharm-Tox Summit March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition and Molecular Gating Conference April 1 - 4, 2024 | 19th Annual Drug Discovery Chemistry April 4 - 7, 2024 | American Physiology Summit April 5 - 10, 2024 | AACR Annual Meeting May 13 - 17, 2024 | 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 7, 2024 | Chemotactic Cytokines June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein Mediated Signaling Networks June 25 - 29, 2024 | FENS Forum 2024 NEW October 2024 | Biologics US 2024 October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs NEW Senior Scientist- Internal Medicine Research Unit NEW Postdoctoral Scholar – Synaptic physiology, optical imaging, substance use disorder, pharmacology Research Fellow Postdoctoral Fellow – Molecular Pharmacology of Feeding Behavior Director of Laboratory Operations - Single-molecule Imaging Center Scientific Assistant Postdoctoral Fellowship- Mechanistic Biology Research Scientist Join Dr. GPCR Ecosystem

Greetings, avid readers! We are thrilled to present our comprehensive GPCR coverage for the week; we have 14 GPCR papers, six industry news, and two job ads. This week's highlight includes congrats to Julia Gardner, Dr. Dylan Scott Eiger, Chloe Hicks,  Dr. Sudarshan Rajagopal, et al. for their finding that GPCR kinases affect biased signaling downstream of CXCR3 based on their location. Drs. Nayara Braga Emidio, Ross Cheloha, Laura M Wingler, et al. for their work on Nanobody-Mediated Dualsteric Engagement. Dr. GPCR Symposia Our upcoming symposium on March 15th is about GPCR activation and signaling. Confirmed speakers include Drs. Franziska Heydenreich, Sudarshan Rajagopal, Graham Ladds, and Michel Bouvier. We will also have a poster session in breakout rooms on Zoom; if you are interested in sharing your work with our community, kindly fill out this form. Additionally, if you participated in our Symposia in 2023, please take a moment to fill out this survey. Dr. GPCR University The past two weeks of the Dr. GPCR University course, 'Applying Pharmacology to Drug Discovery,' led by Dr. Terry Kenakin, have been amazing. Attendees have actively participated in discussions and asked thought-provoking questions. If you missed the chance to register, don't worry! You can still join this waitlist and be the first to know when the live course is offered later this year. Dr. GPCR Volunteers Join our dynamic team as a volunteer! You'll share your contributor articles with the community, stay updated with GPCR literature, join a dynamic team, network with GPCR scientists at our events, and get a complimentary Premium Membership with only 4 hours/monthly commitment on your part. If you are interested in applying, please email us your CV/Resume at  Hello@DrGPCR.com. Dr. GPCR Partnered Events March 5 - 7, 2024 | 3rd GPCRs - Targeted Drug Discovery Summit Join us at the 3rd GPCRs Summit in Boston on March 5-7, 2024. Dr. GPCR Members get 10% off with code MPDRGPCR10. April 22 - 23, 2024 | Endocrine Metabolic GPCRs Join Dr. GPCR founder Dr. Yamina Berchiche at the Endocrine Metabolic GPCRs event in Birmingham, UK, on April 22-23, 2024. Let’s dive into the Classified GPCR News from February 12th to 18th, 2024 GPCR Activation and Signaling Fine-tuning activation specificity of G-protein-coupled receptors via automated path searching Heterotrimeric G protein signaling without GPCRs: the Gα-binding-and-activating (GBA) motif Mechanisms of biased agonism by Gαi/o-biased stapled peptide agonists of the relaxin-3 receptor GPCR kinases differentially modulate biased signaling downstream of CXCR3 depending on their subcellular localization Investigating selectivity and bias for G protein subtypes and β-arrestins by synthetic cannabinoid receptor agonists at the cannabinoid CB1 receptor Why classical receptor theory, which ignores allostery, can effectively measure the strength of an allosteric effect as agonist's efficacy GPCR Binders, Drugs, and more Nanobody-Mediated Dualsteric Engagement of the Angiotensin Receptor Broadens Biased Ligand Pharmacology Pharmacological characterization and radiolabeling of VUF15485, a high-affinity small-molecule agonist for the atypical chemokine receptor ACKR3 GPCRs in Cardiology, Endocrinology, and Taste The Role of G Protein-Coupled Receptors and Receptor Kinases in Pancreatic β-Cell Function and Diabetes GPCRs in Neuroscience Voltage tunes mGlu5 receptor function, impacting synaptic transmission The multifaceted role of the CXC chemokines and receptors signaling axes in ALS pathophysiology Common changes in rat cortical gene expression after antidepressant drug treatment: impacts on metabolism of polyamines, mRNA splicing, regulation of RAS by GAPs, neddylation and GPCR ligand binding GPCRs in Oncology and Immunology Neutrophils are itching to specialize A GPCR-neuropeptide axis dampens hyperactive neutrophils by promoting an alternative-like polarization during bacterial infection Industry News InterAx Biotech's AI platform unlocks new drug designs for diabetes, obesity, and cancer Crinetics Pharmaceuticals to Report Fourth Quarter and Full Year 2023 Financial Results on February 28, 2024 Sosei Heptares Operational Highlights and Consolidated Results for 12 Months ended 31 December 2023 Pioneering Research in GPCR Pharmacology: Unraveling the Secrets of Cellular Communication Bowes Biomedical Investigator Takes Aim at Cracking Cellular Communication Code Aelis Farma will be at Bio Europe Spring in Barcelona GPCR Events, Meetings, and Webinars February 20, 2024 | Career Opportunities in Pharmacology and Drug Discovery March 13 - 15 | 9th German Pharm-Tox Summit March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition and Molecular Gating Conference April 1 - 4, 2024 | 19th Annual Drug Discovery Chemistry April 4 - 7, 2024 | American Physiology Summit April 5 - 10, 2024 | AACR Annual Meeting May 13 - 17, 2024 | 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference and Exhibition June 2 - 7, 2024 | Chemotactic Cytokines June 9 - 14, 2024 | 2024 Phosphorylation and G-Protein Mediated Signaling Networks June 25 - 29, 2024 | FENS Forum 2024 October 2 - 4, 2024 | 9th GPCRs in Medicinal Chemistry October 23 - 25, 2024 | 11th Adhesion GPCR Workshop July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology 2026 GPCR Jobs NEW Research Fellow NEW  Postdoctoral Fellow – Molecular Pharmacology of Feeding Behavior Director of Laboratory Operations - Single-molecule Imaging Center Scientific Assistant Postdoctoral Fellowship- Mechanistic Biology Research Scientist Post-Doc position Join Dr. GPCR Ecosystem