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mechanism of the Delta opioid receptor by an agonist ADL5859 started from inactive conformation using molecular In this study, a DOR agonist ADL5859 was docked to the inactive DOR and multiple microsecond molecular R146, R258 and others) involving in the activation pathway were identified through the conventional molecular

Our previous Markov State Model (MSM) analysis of molecular dynamics simulations of membrane-embedded

August 2022 "Oxysterols induce the migration of B-lymphocytes and dendritic cells to interfollicular regions of lymphoid tissues through binding the EBI2 (GPR183) to stimulate effective adaptive immunity and antibody production during infection. Aberrant EBI2 signaling is implicated in inflammatory bowel disease, sclerosis, and infectious disease. Here, we report the cryo-EM structures of an EBI2-Gi signaling complex with its endogenous agonist 7α,25-OHC and that of an inactive EBI2 bound to the inverse agonist GSK682753A. These structures reveal an agonist binding site for the oxysterol and a potential ligand entrance site exposed to the lipid bilayer. Mutations within the oxysterol binding site and the Gαi interface attenuate G protein signaling and abolish oxysterol-mediated cell migration indicating that G protein signaling directly involves in the oxysterol-EBI2 pathway. Together, these findings provide new insight into how EBI2 is activated by an oxysterol ligand and will facilitate the development of therapeutic approaches that target EBI2-linked diseases." Read more at the source #DrGPCR #GPCR #IndustryNews

August 2022 "G-protein-coupled receptors (GPCR) are present at the cell surface in different conformational and oligomeric states. However, how these states impact GPCRs biological function and therapeutic targeting remains incompletely known. Here, we investigated this issue in living cells for the CC chemokine receptor 5 (CCR5), a major receptor in inflammation and the principal entry co-receptor for Human Immunodeficiency Viruses type 1 (HIV-1). We used TIRF microscopy and a statistical method to track and classify the motion of different receptor subpopulations. We showed a diversity of ligand-free forms of CCR5 at the cell surface constituted of various oligomeric states and exhibiting transient Brownian and restricted motions. These forms were stabilized differently by distinct ligands. In particular, agonist stimulation restricted the mobility of CCR5 and led to its clustering, a feature depending on β-arrestin, while inverse agonist stimulation exhibited the opposite effect. These results suggest a link between receptor activation and immobilization. Applied to HIV-1 envelope glycoproteins gp120, our quantitative analysis revealed agonist-like properties of gp120s. " Read more at the source #DrGPCR #GPCR #IndustryNews

August 2022 "The apelin receptor (APJ) is a target for cardiovascular indications. Previously, we had identified a novel pyrazole-based agonist 1 ((S)-N-(1-(cyclobutylamino)-1-oxo-5-(piperidin-1-yl)pentan-3-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide hydrochloride) of this GPCR. Systematic modification of 1 was performed to produce compounds with improved potency and ADME properties. Orally bioavailable compound 47 with favorable agonist potency (Ca2+EC50 = 24 nM, cAMPi EC50 = 6.5 nM) and pharmacokinetic properties (clearance ∼20 mL/min/kg in rats) was identified. This compound has vastly reduced brain penetration and is devoid of significant off-target liability. In summary, a potent and selective APJ agonist suitable for in vivo studies of APJ in peripheral tissues after oral administration has been identified." Read more at the source #DrGPCR #GPCR #IndustryNews

August 2022 "Chemokines, a subgroup of cytokines along with their receptors, are involved in various biologic processes and regulation of a wide range of immune responses in different physiologic and pathologic states such as tissue repair, infection, and inflammation. C-X-C motif chemokine receptor 4 (CXCR4), a G-protein-coupled receptor (GPCR), has one identified natural ligand termed stromal-derived factor-1(SDF-1 or CXCL12). Evidence demonstrated that the ligation of SDF-1 to CXCR4 initiates several intracellular signaling pathways, regulating cell proliferation, survival, chemotaxis, migration, angiogenesis, adhesion, as well as bone marrow (BM)-resident cells homing and mobilization. Additionally, CXCR4 is expressed by tumor cells in blood malignancies and solid tumors." Read more at the source #DrGPCR #GPCR #IndustryNews

The computational modeling and the 1.5-μs molecular dynamics data presented in the current study are

August 2022 "The X-linked form of Kallmann syndrome (KS), characterized by hypogonadotropic hypogonadism and anosmia, is due to mutations in the ANOS1 gene that encodes for the extracellular matrix (ECM) protein anosmin 1. Prokineticins (PKs) exert their biological functions through the activation of the G protein-coupled receptors (GPCRs) prokineticin receptor 1 and 2 (PKR1, 2), and mutations in the PK2 and PKR2 genes are involved in the pathogenesis of KS. We have previously shown interaction between PKR2 and anosmin 1 in vitro. In the current report we present evidence of the modulation of PK2/PKR2 activity by anosmin 1, since this protein is able to enhance the activation of the ERK1/2 (extracellular signal-regulated kinase 1/2) pathway elicited by PK2 through PKR2. We also show that the N-terminal region of anosmin 1, capable of binding to the PK2-binding domain of PKR2, seems to be responsible for this effect. The whey acidic protein domain (WAP) is necessary for this modulatory activity, although data from GST pull-down (glutathione-S-transferase) and analysis of the N267K mutation in the fibronectin type III domain 1 (FnIII.1) suggest the cysteine-rich (CR) and the FnIII.1 domains could assist the WAP domain both in the binding to PKR2 and in the modulation of the activation of the receptor by PK2. Our data support the idea of a modulatory role of anosmin 1 in the biological effects controlled by the PK2/PKR2 system." Read more at the source #DrGPCR #GPCR #IndustryNews

Electron cryo-microscopy (cryo-EM) is a powerful technique for the structural characterization of biological macromolecules, enabling high-resolution analysis of targets once inaccessible to structural interrogation. In recent years, pharmaceutical companies have begun to utilize cryo-EM for structure-based drug design. Structural analysis of integral membrane proteins, which comprise a large proportion of druggable targets and pose particular challenges for X-ray crystallography, by cryo-EM has enabled insights into important drug target families such as G protein-coupled receptors (GPCRs), ion channels, and solute carrier (SLCs) proteins. Structural characterization of biologics, such as vaccines, viral vectors, and gene therapy agents, has also become significantly more tractable. As a result, cryo-EM has begun to make major impacts in bringing critical therapeutics to market. In this review, we discuss recent instructive examples of impacts from cryo-EM in therapeutics design, focusing largely on its implementation at Pfizer. We also discuss the opportunities afforded by emerging technological advances in cryo-EM, and the prospects for future development of the technique. Read full article

August 2022 Production of human A 2A AR in lipid nanodiscs for 19 F-NMR and single-molecule fluorescence A2A adenosine receptor (A2AAR), a class A G protein-coupled receptor (GPCR) for 19F-NMR and single-molecule

Hence, we performed extensive large-scale molecular dynamics (MD) simulations of the GPR97-Go complex

August 2022 GPCRs steer G i and G s selectivity via TM5-TM6 switches as revealed by structures of serotonin receptors "Serotonin (or 5-hydroxytryptamine, 5-HT) is an important neurotransmitter that activates 12 different G protein-coupled receptors (GPCRs) through selective coupling of Gs, Gi, or Gq proteins. The structural basis for G protein subtype selectivity by these GPCRs remains elusive. Here, we report the structures of the serotonin receptors 5-HT4, 5-HT6, and 5-HT7 with Gs, and 5-HT4 with Gi1. The structures reveal that transmembrane helices TM5 and TM6 alternate lengths as a macro-switch to determine receptor's selectivity for Gs and Gi, respectively. We find that the macro-switch by the TM5-TM6 length is shared by class A GPCR-G protein structures. Furthermore, we discover specific residues within TM5 and TM6 that function as micro-switches to form specific interactions with Gs or Gi. Together, these results present a common mechanism of Gs versus Gi protein coupling selectivity or promiscuity by class A GPCRs and extend the basis of ligand recognition at serotonin receptors." Read more at the source #DrGPCR #GPCR #IndustryNews

GPCR Podcast : The Future of GPCR Drug Discovery with Molecular Modeling The field of GPCR research is

October 2022 "G protein-coupled receptors (GPCRs) are important drug targets characterized by a canonical seven transmembrane (TM) helix architecture. Recent advances in X-ray crystallography and cryo-EM have resulted in a wealth of GPCR structures that have been used in drug design and formed the basis for mechanistic activation hypotheses. Here, ensemble refinement (ER) of crystallographic structures is applied to explore the impact of binding of agonists and antagonist/inverse agonists to selected structures of cannabinoid receptor 1 (CB1R), β2 adrenergic receptor (β2 AR) and A2A adenosine receptor (A2A AR). " Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 "Study of small molecule binding to live cells provides important information on the characterization

From microsecond-length unbiased molecular dynamics simulations, we found that the presence of the CBD Our work will pave the way for understanding the CBD pharmacology at a molecular level and aid in harnessing

Watch Episode 170 Thinking Differently Pain research has long followed a familiar route: from molecule This approach reflects his focus on developing models that behave  like patients before molecular exploration Rather than starting with a molecular hypothesis, Serafini’s team noticed that hamsters infected with expression signatures  linked to pain, without being constrained by pre-existing assumptions about which molecular It asks researchers to consider the entire ecosystem: from patient to molecule , not just the other way

With insights from molecular dynamics, biased signaling, and allosteric modulation, this session lays research—delivered in a format that’s as approachable as it is transformative. 👉 Ready to understand what your molecules

Bryan Roth and Brian Krumm for their study on Molecular glues as potential GPCR therapeutics Drs. potential therapeutic target for neurological and psychiatric disorders GPCR Activation and Signaling Molecular the GPCR-dependent translatome via site-selective activation of mTOR GPCR Binders, Drugs, and more Molecular study Monitoring norepinephrine release in vivo using next-generation GRABNE sensors Structural and Molecular Drug Discovery Biologist HIGHLIGHT Principal Scientist, In vitro pharmacology Post-Doctoral Scientist- Molecular

Our model not only shows the function of dimeric β2-AR but also provides a molecular insight into the

Mediated Early Conformational Changes in the Process of Light-Induced Green Cone Pigment Activation Molecular acting on GPCRs Molecular characterization of recombinant LSDV isolates from 2022 outbreak in Indonesia 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, physiology, optical imaging, substance use disorder, pharmacology Research Fellow Postdoctoral Fellow – Molecular

Based on an ingenious combination of multicolor single-molecule microscopy approach with molecular dynamics However, the evidence obtained in this study proposes novel molecular mechanisms in which β-arrestin Read the complete article here: https://www.ecosystem.drgpcr.com/gpcr-binders-drugs-and-more/in-depth-molecular-profiling-of-an-intronic-gnao1 Molecular mechanism of GPCR-mediated arrestin activation. Molecular mechanism of b-arrestin-biased agonism at seven-transmembrane receptors. Annu. Rev.

The therapeutic approaches mainly include small molecule inhibitors, as well as monoclonal antibodies At a molecular level, different ligands bind to the same receptor and vice-versa (Marcuzzi et al. 2018 On the other hand, Shall and Proudfoot excluded the idea of molecular redundancy, pointing out that, Subsequent reports characterizing small molecule agonists for CXCR3 further substantiated the notion the use of engineered chemokine analogs which are analogs of the natural ligands, allowing a better molecular

Gabriele Kockelkoren's contribution as first-author on "Molecular mechanism of GPCR spatial organization GPCR Symposium on Structural and Molecular Insights on GPCR Activation was a success! Structural and Molecular Insights into GPCR Function Molecular mechanism of GPCR spatial organization Months Cumulus Oncology and Leadxpro collaborate on small molecules targeting cancer-focused GPCR. GPCR) Postdoctoral Fellow, Caron Lab Clinical Trial Associate Research Scientist/Senior Scientist I - Molecular

Allow registrants to appreciate the incredible versatility of GPCRs and how small molecules can affect Emerging Voices in GPCR Biology in Special Issue of Molecular Pharmacology GPCR Events, Meetings, and HIGHLIGHT Senior Scientist, GPCR Pharmacology Research Associate - Professor Graeme Milligan Postdoc in Molecular receptor signaling kinetics and concentration-dependent responses using ONE-GO biosensors Structural and Molecular the serotonin1A receptor Potential allosteric pockets identification of glucagon receptor based on molecular

sliding and orientational selection supporting complex formation of a GPCR and a middle sized flexible molecule "A GA-guided multidimensional virtual-system coupled molecular dynamics (GA-mD-VcMD) simulation was conducted to elucidate binding mechanisms of a middle-sized flexible molecule, bosentan, to a GPCR protein All molecular components (bosentan, hETB, membrane, and solvent) were represented with an all-atom model the binding pocket from outside to inside of the pocket with an accompanying rapid reduction of the molecular

Intermolecular Interactions in G Protein-Coupled Receptor Allosteric Sites at the Membrane Interface from Molecular interactions and stability, the binding site structure, and how all of these are affected by lipid molecules interactions in the allosteric sites of the PAR2, C5aR1, and GCGR receptors in three lipid compositions using molecular The availability of polar atoms for interactions in such cavities can be assessed by water molecules

target Sustained antidepressant effects of ketamine metabolite involve GABAergic inhibition-mediated molecular LSDV) infection in domestic Himalayan yaks (Bos grunniens) in Himachal Pradesh, India Structural and Molecular 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, physiology, optical imaging, substance use disorder, pharmacology Research Fellow Postdoctoral Fellow – Molecular

) spectroscopy allows the determination of atomic-level information on intermolecular interactions, molecular structure, and molecular dynamics in the cellular environment. This may be broadly divided into studies focused on obtaining detailed molecular information in the intracellular context ("in-cell") or those focused on characterizing molecules or events at the cell surface ("on-cell provide a brief survey of the applicability of on-cell NMR approaches to other classes of cell surface molecules

team study on 'Location bias: A "Hidden Variable" in GPCR pharmacology' Yao Lu and colleagues work on 'Molecular Expression in the Testis of Infertile Patients with Nonobstructive Azoospermia GPCRs in Neuroscience Molecular of Modern GPCR Drug Discovery Location bias: A "Hidden Variable" in GPCR pharmacology Structural and Molecular | SLAS2024 International Conference and Exhibition NEW March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar NEW March 24 - 29, 2024 | Ligand Recognition and Molecular Gating Conference NEW April