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Here, we discuss recent crystal structures of inactive C5aR1 in terms of an inverted orientation of helix H8, unobserved in other GPCR structures.

While others refined lab techniques, he found himself gravitating toward structural models in his spare He was naturally drawn to analyzing solved protein structures—an activity that, unbeknownst to him, was At the time, there were no solved structures of GPCRs readily available, so his work remained disconnected At that point, very few GPCR crystal structures had been determined. increasingly depend on those who can unite modeling with experimentation, turning predictions into real therapeutic

August 2022 "Single particle cryogenic-electron microscopy (cryo-EM) is used extensively to determine structures However, applying it to GPCRs without signaling proteins remains challenging because most receptors lack structural Although a similar strategy has the potential to broadly facilitate cryo-EM structure determination of Here, we address this shortcoming by exploring different fusion protein designs, which lead to structures

adipose tissue size more effectively than exendin, suggesting that biased agonism can lead to distinct therapeutic In conclusion, biased agonism at the GLP-1R represents a promising strategy for optimizing therapeutic continues to grow, it is likely to play an increasingly important role in the design of next-generation therapeutics Christopoulos, Signalling bias in new drug discovery: detection, quantification and therapeutic impact Drucker, D.J., Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1.  

While experimentalists struggled for months with crystallography, he could pull a clean protein structure They offer extraordinary therapeutic promise —but their complexity makes them one of the hardest targets Structural biologists may capture snapshots of receptor conformations, but lack large-scale screening The most effective discovery programs are structured like Carlsson’s: modeling designed with downstream Discover Drugs—People Do In GPCR research, the biggest breakthroughs won’t come from algorithms or crystal structures

Yet even with the structural biology revolution, one stubborn hurdle persists: prediction.   Can we leverage structural and computational insights not just to explain receptor–ligand interactions His lab sits at the crossroads of structure-based modeling, computational chemistry, and drug discovery Fast forward to today: dozens of GPCR structures  exist, many in multiple conformations or bound to G The next frontier in GPCR drug discovery isn’t more structures—it’s smarter models.

The experimental structure of these receptors has yet to be determined, and key-residues controlling

Recurrent high-impact mutations at cognate structural positions in class A G protein-coupled receptors They have a common structure and, signaling through a much smaller set of G proteins, arrestins, and cognate positions across GPCR paralogs opens a window into cancer mechanisms and potential approaches to therapeutics

A New Wave of GPCR Drug Discovery GPCRs are considered highly druggable, with GPCR-targeting therapeutics Within the last two years, three investments stand out: · Tectonic Therapeutics: received $80 USD Series A round to develop small molecule drugs against difficult-to-drug GPCRs. · Domain Therapeutics Developing Small Protein Therapeutics with a Novel Discovery Platform One way to overcome the challenges About Orion Biotechnology Orion’s mission is to unlock the therapeutic potential of previously undruggable

July 2022 "July 19, 2022 07:00 AM Eastern Daylight Time BOSTON--Tectonic Therapeutic, Inc. a pre-clinical

Sandra Berndt talk about new structural perspectives in GPCR-mediated Src family kinase activation.

February 2022 "Ermium Therapeutics Announces the Formation of a Scientific Advisory Board comprising

Essential Frameworks for Precision Drug Discovery: An Insight into Advanced Strategies for Targeted Therapeutics

This week's highlights: Kudos to our partner, GPCR Therapeutics, for partnering with Bridge Biotherapeutics acids conjugation with [Cp*Rh(H2O)3]2+ by using the meta-dynamics/FMO3 approach Industry News GPCR Therapeutics Therapeutics - Providing the next generation of high-impact medicines Structure Therapeutics Provides Study Neurocrine opening two Phase 1 trials in oral Parkinson’s therapies Bearing Fruit: Deep Apple Therapeutics Launches to Screen AI-Generated Virtual Libraries AbbVie to Acquire Cerevel Therapeutics in Transformative

accurately reflect native biological processes and preclinical research can more reliably translate into therapeutic Trends in clinical success rates and therapeutic focus. Endosomal signaling of delta opioid receptors is an endogenous mechanism and therapeutic target for relief Cryo-EM structures of GPCRs coupled to Gs, Gi and Go. Structural insights into G protein activation by D1 dopamine receptor.

GPCR Activation and Signaling Therapeutic antagonism of the neurokinin 1 receptor in endosomes provides muscarinic receptor elucidated through structure and dynamics. Industry News Structure Therapeutics Announces Poster Presentations of its Oral GLP-1 Receptor Agonist GSBR-1290 at the American Diabetes Association 83rd Scientific Sessions Domain Therapeutics' Nomination of DT-9045: A Groundbreaking NAM for Immunooncology Structure Therapeutics to Present at Jefferies Healthcare

May 2022 "Seoul, South Korea, 28 April 2022 – GPCR therapeutics, Inc., a venture-backed clinical stage

its best-in-class and first-in-class immuno-oncology programs STRASBOURG, France & MONTREAL- Domain Therapeutics

Thus, identifying novel molecular targets for developing HF therapeutics remains a key research focus Additionally, GPCR dysregulation underlies multiple models of cardiac pathology, and most pharmacological therapeutics This perspective reviews cardiac GPCRs, describes the structure and functions of GRK2 in cardiac function

September 2022 "G protein‐coupled receptors (GPCRs) are valuable therapeutic targets for many diseases We hypothesized that there is a common set of receptor interactions made by ligands of diverse structures We computationally docked ~2700 known β2AR ligands to multiple β2AR structures, generating ca 75 000 interpretation of ML analysis in human understandable form allowed us to construct an exquisitely detailed structure‐activity

bioinformatics tools showed that functional mutations in the ADGLR3 gene disrupt the standard and wild ADGRL3 structure

Historically, ligands for GPCRs have been identified before their receptor counterparts. With the cloning revolution, several unidentified receptors have been found and were labelled as “orphan” for their endogenous ligands. Orphan GPCRs have been shown to play key roles in various physiological functions, such as sensory perception, reproduction, development, growth, metabolism, and are also linked to major diseases, such as neuroinflammatory, metabolic and autoimmune diseases. Therefore, matching a ligand to an orphan GPCRs, the process of de-orphanizing, is of great importance in order to better understanding human physiology as well as to dissect the molecular mechanism governing the involvement of these receptors in human pathology. GPR84 is an example of an orphan GPCR (Sharman et al., 2011), although it is widely accepted that medium‐chain fatty acids (MCFAs) can bind to and activate this receptor with modest potency. GPR84 is a Gi‐coupled class A GPCR mainly expressed in immune cells and microglia in the brain (Wojciechowicz & Ma'ayan, 2020). GPR84 has been shown to be an attractive target in pro‐inflammatory conditions (Gagnon et al., 2018; Suzuki et al., 2013; Vermeire et al., 2017; Wojciechowicz & Ma'ayan, 2020) and efforts have been made to discover GPR84 antagonists. In this study Marsango et al. address two key questions in GPR84 biology and pharmacology: 1. how GPR84 expression profile correlates with physiological and pathological conditions? and 2. which ligands can be used as tool compounds to study the function and biology of this receptor? Regarding the first question, GPR84 overexpression in immune cells in a range of pro‐inflammatory disorders renders it a promising target in inflammatory and fibrotic conditions, including neuroinflammation (Audoy‐Remus et al., 2015), with ongoing clinical trials in idiopathic pulmonary fibrosis (Labéguère et al., 2014). GPR84 has been additionally proposed to be a potential biomarker in different inflammatory diseases (Arijs et al., 2011; Planell et al., 2017). Some studies have also reported GPR84 involvement in pain, atherosclerosis, and even metabolic disorders (Nicol et al., 2015, Audoy‐Remus et al., 2015, Du Toit et al., 2018). Regarding the second question, there is still a lot to be done in respect to tool compounds to study the function of this receptor towards clinical validation, as well as radiopharmaceuticals, including potential PET ligands, and suitable antibodies. Recent work has shown distinct functional outcomes of agonist ligands (Pillaiyar et al., 2018) with biased properties which can help to better elucidate the molecular pharmacology of this receptor. In addition, several GPR84 ligands have been described as well as GPR84 knockout mice. Among these ligands are orthosteric agonists such as alkylpyrimidine‐4,6‐diol derivatives (Liu et al., 2016; Zhang et al., 2016) and embelin (2,5‐dihydroxy‐3‐undecyl‐1,4‐benzoquinone) which is a natural product derived from the plant Embelia ribes (Gaidarov et al., 2018) which agonizes GPR84 but, interestingly, blocks the chemokine receptor CXCR2 and the adenosine A3 receptor (Gaidarov et al., 2018). IM (3,3′‐methylenebis‐1H‐indole) has been identified as a positive allosteric modulator of GPR84, a metabolite produced in vivo from indole‐3‐carbinol, which is present at high levels in some vegetables including broccoli and kale (Wang, Schoene, Milner, & Kim, 2012, Köse et al., 2020). GPR84 antagonists include a series of dihydropyrimidinoisoquinolinones (Labéguère et al., 2014), which behave as non‐competitive antagonists of GPR84 (Labéguère et al., 2020). From these series of compounds, GLPG1205 progressed into clinical development for the potential treatment of ulcerative colitis although it did not demonstrate sufficient efficacy (Labéguère et al., 2020). Overall, GPR84 is a promising target to exploit and the investment in better tools to study its function in both disease and physiological settings will likely potentiate drug discovery campaigns against this orphan GPCR. Check the original article at here! #GPCR #DrGPCR#Ecosystem

August 2022 "Histamine exerts its physiological functions through its four receptor subtypes. In this work, we report the subcellular localization of histamine receptor 2 (H2R), a G protein-coupled receptor (GPCR), which is expressed in a wide variety of cell and tissue types. A growing number of GPCRs have been shown to be localized in the nucleus and contribute toward transcriptional regulation. In this study, for the first time, we demonstrate the nuclear localization of H2R in lymphatic endothelial cells. In the presence of its ligand, we show significant upregulation of H2R nuclear translocation kinetics. Using fluorescently tagged histamine, we explored H2R-histamine binding interaction, which exhibits a critical role in this translocation event. Altogether, our results highlight the previously unrecognized nuclear localization pattern of H2R. At the same time, H2R as a GPCR imparts many unresolved questions, such as the functional relevance of this localization, and whether H2R can contribute directly to transcriptional regulation and can affect lymphatic specific gene expression. H2R blockers are commonly used medications that recently have shown significant side effects. Therefore, it is imperative to understand the precise molecular mechanism of H2R biology. In this aspect, our present data shed new light on the unexplored H2R signaling mechanisms. This article has an associated First Person interview with the first author of the paper." Read more at the source #DrGPCR #GPCR #IndustryNews

That choice determines whether you risk over- or under-dosing, miss safety windows, or miss therapeutic For teams building structure–activity relationships (SAR), this insight is gold: you’re not just chasing More nuanced control, fewer off-target liabilities, and novel therapeutic windows. Correctly distinguishing these mechanisms helps refine therapeutic index calculations, prioritize safer

However, how these states impact GPCRs biological function and therapeutic targeting remains incompletely

We discuss ligand binding, signaling, and structures of the vGPCRs in light of robust differences from Finally, we briefly discuss the therapeutic targeting of vGPCRs as future treatment of acute and chronic

GPCR Symposium on Structural and Molecular Insights on GPCR Activation. GPCRs in Neuroscience Orphan receptor GPR88 as a potential therapeutic target for CNS disorders - an Industry News Coherus to Acquire Surface Oncology Confo Therapeutics and AbCellera partner on GPCR-targeting Therapeutics listed on Nasdaq GPCR Events, Meetings, and Webinars NEW FREE ERNEST ECI zoominar (June (June 28 - 30, 2023) NEW FREE Seminar Antibodies targeting Membrane Proteins - From Antigen to New Therapeutics

April 2022 Ono Enters into Collaboration Agreement with Domain Therapeutics and Université de Montréal : Gyo Sagara; “Ono”) today announced that it has newly signed a collaboration agreement with Domain Therapeutics

But for Ajay Yekkirala, that closed door lit the fuse for a career that would reimagine GPCR therapeutics was a scientific journey that now spans two biotech startups, and a bold reimagining of GPCR-targeted therapeutics Blue Therapeutics: Turning GPCR Biology Into a Business Ajay’s academic training planted the seeds for Despite decades of progress in structural biology and pharmacology, predicting how  a GPCR will respond co-founded Superluminal Medicines , a biotech company focused on integrating machine learning with structural

To better understand the structural basis for this bias, we examined structural models of GPR35 and conducted