The molecular diversity of GPCR signaling systems is likely to be closely associated with disease-associated

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

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

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

However, it is becoming increasingly clear that GPCRs show great diversity in their intracellular location Here we will discuss recent studies on the diversity of location, effectors, and signaling of GPCRs,

We also synthesized a series of small molecule ligands which acted as selective agonists for ACKR3 as Using select point mutations, we studied the molecular characteristics that determine the ability of small molecules to activate ACKR3 receptors, revealing a key role for the deeper binding pocket composed novel selective ligands for ACKR3 were discovered and the site of interactions between these small molecules

Small molecules biasedly modulating the TLR4 signaling axis not only provide probes to fine-tune receptor

October 2022 "Single-molecule counting techniques enable a precise determination of the intracellular in receptor signaling came from ensemble biochemical and biophysical assays, innovations in single-molecule Here, we review recent developments in single-molecule counting with a focus on photobleaching step counting and the emerging technique of quantitative single-molecule localization microscopy-with a particular

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

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

September 2022 Divergent roles for the gut intraepithelial lymphocyte GLP-1R in control of metabolism

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

The GPCR Opportunity GPCRs are the largest and most diverse group of membrane receptors. The engineered analog approach involves optimizing this scaffold, adding and subtracting molecular contacts diversity focused into the part of the ligand that engages the TM domain. single discovery campaign (CCR5 is shown as an example), Orion’s PROcisionXᵀᴹ platform generates a diverse This, together with the rapid development of artificial intelligence (AI)-driven in silico-based molecular

noticeably, these interactions are not limited to members of the same family, but involve receptors as diverse the physiological and pathological relevance of these interactions, since this additional level of molecular and signaling pathways is only beginning to be explored and represents a novel mechanism providing diversity

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! GPCRome-wide analysis of G-protein-coupling diversity using a computational biology approach. Structural and Molecular Insights into GPCR Function Molecular mechanism of GPCR spatial organization GPCR) Postdoctoral Fellow, Caron Lab Clinical Trial Associate Research Scientist/Senior Scientist I - Molecular

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 Discovery Biologist   HIGHLIGHT   Principal Scientist, In vitro pharmacology   Post-Doctoral Scientist- Molecular

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 Computational Chemistry Postdoc in GPCR mechanosensing   Postdoctoral Position GPCR Activation and Signaling Diverse 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

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 Molecular mechanism of GPCR-mediated arrestin activation. Molecular mechanism of b-arrestin-biased agonism at seven-transmembrane receptors. Annu. Rev. Diversity and specificity in the regulated endocytic membrane trafficking of G-protein-coupled receptors

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 Insights into GPCR Function Exploring Diverse Signaling Mechanisms of G Protein-Coupled Receptors through 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,

Reviews, GPCRs, and more The diversity of invertebrate visual opsins spanning Protostomia, Deuterostomia Structural and Molecular Insights into GPCR Function Computational investigation of functional water Molecular insights into the mechanism of sugar-modified enkephalin binding to opioid receptors. Current Technologies To Understand G-Protein-Coupled Receptor Molecular Pharmacology. June 4-8,2023. 2023 Molecular Pharmacology (GRS) Seminar GRC. June 10 - 11.

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

Dicovalent Ligands for the Adenosine A1 Receptor Bryan Roth  and Brian Krumm  for their excellent study on Molecular Emerging Voices in GPCR Biology in Special Issue of Molecular Pharmacology GPCR Events, Meetings, and Pharmacology GPCR Jobs HIGHLIGHT Research Associate - Professor Graeme Milligan HIGHLIGHT Postdoc in Molecular through positive allosteric modulation of the prostaglandin EP4 receptor GPCR Binders, Drugs, and more Molecular Endocrinology, and Taste Ciliary localization of GPR75 promotes fat accumulation in mice GPCRs in Neuroscience Diverse

receptor MRGPRX1 Improved approaches to channel capacity estimation discover compromised GPCR signaling in diverse ventral tegmental area dopamine neurons and dopamine release in the nucleus accumbens Understanding the Molecular manipulation of Gq- and Gi/o-coupled receptor signaling in neurons and heart muscle cells Structural and Molecular structure determination of GPCRs in various states Apelin receptor dimerization and oligomerization Molecular Associate Postdoc Research Associate Director, Regulatory Affairs Research Scientist/Senior Scientist I - Molecular

Grotsch, Bryan L Roth, Valery V Fokin  et al. for their research on Virtual Screening of a Chemically Diverse Marina Casiraghi, Robert J Lefkowitz, Peter Gmeiner, Brian K Kobilka et al. for their investigation on Molecular GPCR Symposia Join us on June 7th for our next symposium on Structural and Molecular Insights into GPCR role for Gβγ subunit instead of cAMP GPCR Binders, Drugs, and more Virtual Screening of a Chemically Diverse Insights into GPCR Function Molecular insights into G protein coupling specificity at a class A GPCR

Tobias Langenhan for his papers to highlight suggestions GAIN Domain Unfolding in Adhesion GPCRs Molecular Severity Unveiling Mechanical Activation: GAIN Domain Unfolding and Dissociation in Adhesion GPCRs Molecular Drosophila melanogaster Reviews, GPCRs, and more Catecholamine Derivatives: Natural Occurrence, Structural Diversity characterization of lumpy skin disease virus from recent outbreaks in Pakistan Structural and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition and Molecular Gating Conference April 1 - 4,

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