September 2022 "Metabotropic γ-aminobutyric acid receptor (GABABR), a class C G protein-coupled receptor (GPCR) heterodimer, plays a crucial role in the central nervous system. Cryo-electron microscopy studies revealed a drastic conformational change upon activation and a unique G protein (GP) binding mode. However, little is known about the mechanism for GP coupling and activation for class C GPCRs. Here, we use molecular metadynamics computations to predict the mechanism by which the inactive GP induces conformational changes in the GABABR transmembrane domain (TMD) to form an intermediate pre-activated state. We find that the inactive GP first interacts with TM3, which further leads to the TMD rearrangement and deeper insertion of the α5 helix that causes the Gα subunit to open, releasing GDP, and forming the experimentally observed activated structure. This mechanism provides fresh insights into the mechanistic details of class C GPCRs activation expected to be useful for designing selective agonists and antagonists." Read more at the source #DrGPCR #GPCR #IndustryNews

GPCRs Are Optimal Regulators of Complex Biological Systems and Orchestrate the Interface between Health physiological balance between healthy and pathological conditions; thus, their importance in systems biology

., of the University of Oxford , has joined Exscientia as Chief Scientist of Biologics AI.

Extensive efforts of structural biology have been made on the study of GPCRs.

Electron cryo-microscopy (cryo-EM) is a powerful technique for the structural characterization of biological Structural characterization of biologics, such as vaccines, viral vectors, and gene therapy agents, has

G protein-coupled receptors (GPCRs) transmit extracellular signals to the inside by activation of intracellular effector proteins. Different agonists can promote differential receptor-induced signaling responses - termed bias - potentially by eliciting different levels of recruitment of effector proteins. As activation and recruitment of effector proteins might influence each other, thorough analysis of bias is difficult. Here, we compared the efficacy of seven agonists to induce G protein, G protein-coupled receptor kinase 2 (GRK2), as well as arrestin3 binding to the muscarinic acetylcholine receptor M3 by utilizing FRET-based assays. In order to avoid interference between these interactions, we studied GRK2 binding in the presence of inhibitors of Gi and Gq proteins and analyzed arrestin3 binding to prestimulated M3 receptors to avoid differences in receptor phosphorylation influencing arrestin recruitment. We measured substantial differences in the agonist efficacies to induce M3R-arrestin3 versus M3R-GRK2 interaction. However, the rank order of the agonists for G protein- and GRK2-M3R interaction was the same, suggesting that G protein and GRK2 binding to M3R requires similar receptor conformations, whereas requirements for arrestin3 binding to M3R are distinct. Read full article

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October 2022 High hedgehog signaling is transduced by a multikinase-dependent switch controlling the apico-basal distribution of the GPCR smoothened "The oncogenic G-protein-coupled receptor (GPCR) Smoothened (SMO) is a key transducer of the hedgehog (HH) morphogen, which plays an essential role in the patterning of epithelial structures. Here, we examine how HH controls SMO subcellular localization and activity in a polarized epithelium using the Drosophila wing imaginal disc as a model. We provide evidence that HH promotes the stabilization of SMO by switching its fate after endocytosis toward recycling. This effect involves the sequential and additive action of protein kinase A, casein kinase I, and the Fused (FU) kinase. Moreover, in the presence of very high levels of HH, the second effect of FU leads to the local enrichment of SMO in the most basal domain of the cell membrane. Together, these results link the morphogenetic effects of HH to the apico-basal distribution of SMO and provide a novel mechanism for the regulation of a GPCR." Read more at the source #DrGPCR #GPCR #IndustryNews

Bitter taste receptors (TAS2Rs) are a poorly understood subgroup of G protein-coupled receptors (GPCRs). The experimental structure of these receptors has yet to be determined, and key-residues controlling their function remain mostly unknown. We designed an integrative approach to improve comparative modeling of TAS2Rs. Using current knowledge on class A GPCRs and existing experimental data in the literature as constraints, we pinpointed conserved motifs to entirely re-align the amino-acid sequences of TAS2Rs. We constructed accurate homology models of human TAS2Rs. As a test case, we examined the accuracy of the TAS2R16 model with site-directed mutagenesis and in vitro functional assays. This combination of in silico and in vitro results clarifies sequence-function relationships and proposes functional molecular switches that encode agonist sensing and downstream signaling mechanisms within mammalian TAS2Rs sequences. Read full article

October 2022 Regulation of pulmonary surfactant by the adhesion GPCR GPR116/ADGRF5 requires a tethered agonist-mediated activation mechanism "The mechanistic details of the tethered agonist mode of activation for the adhesion GPCR ADGRF5/GPR116 have not been completely deciphered. We set out to investigate the physiological importance of autocatalytic cleavage upstream of the agonistic peptide sequence, an event necessary for NTF displacement and subsequent receptor activation. To examine this hypothesis, we characterized tethered agonist-mediated activation of GPR116 in vitro and in vivo. A knock-in mouse expressing a non-cleavable GPR116 mutant phenocopies the pulmonary phenotype of GPR116 knock-out mice, demonstrating that tethered agonist-mediated receptor activation is indispensable for function in vivo. Using site-directed mutagenesis and species-swapping approaches, we identified key conserved amino acids for GPR116 activation in the tethered agonist sequence and in extracellular loops 2/3 (ECL2/3). We further highlight residues in transmembrane 7 (TM7) that mediate stronger signaling in mouse versus human GPR116 and recapitulate these findings in a model supporting tethered agonist:ECL2 interactions for GPR116 activation." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 "We describe production of the human A2A adenosine receptor (A2AAR), a class A G protein-coupled receptor (GPCR) for 19F-NMR and single-molecule fluorescence (SMF) spectroscopy. We explain in detail steps shared between the two sample preparation strategies, including expression and isolation of A2AAR and assembly of A2AAR in lipid nanodiscs and procedures for incorporation of either 19F-NMR or fluorescence probes. Protocols for SMF experiments include sample setup, data acquisition, data processing, and error analysis. For complete details on the use and execution of this protocol, please refer to Wei et al. (2022) and Sušac et al. (2018)." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 "The follicle-stimulating hormone receptor (FSHR) belongs to the glycoprotein hormone receptors, a subfamily of G-protein-coupled receptors (GPCRs). FSHR is involved in reproductive processes such as gonadal development and maturation. Structurally, the extensive extracellular domain, which contains the hormone-binding site and is linked to the transmembrane domain by the hinge region (HR), is characteristic for these receptors. How this HR is involved in hormone binding and signal transduction is still an open question. We combined in vitro and in situ chemical crosslinking, disulfide pattern analysis, and mutation data with molecular modeling to generate experimentally driven full-length models. These models provide insights into the interface, important side-chain interactions, and activation mechanism. The interface indicates a strong involvement of the connecting loop. A major rearrangement of the HR seems implausible due to the tight arrangement and fixation by disulfide bonds. The models are expected to allow for testable hypotheses about signal transduction and drug development for GPHRs." Read more at the source #DrGPCR #GPCR #IndustryNews

This key event will delve into adhesion GPCR Biology. in Oncology and Immunology Metabolic crosstalk: Extracellular ATP and the tumor microenvironment in cancer progression and therapy Agonists of galanin subtype 2 receptor may prevent pancreatic cancer and agonists of angiotensin II type 2 receptor may prevent colorectal cancer Distinct Activation Mechanisms of CXCR4 Director GPCR Drug Discovery Biologist   HIGHLIGHT   Principal Scientist, In vitro pharmacology   Post-Doctoral

Mexico City from October 23 to 25, 2024, and will be a cornerstone for discussions in adhesion GPCR Biology Metallo-protease Peptidase M84 from Bacillusaltitudinis induces ROS-dependent apoptosis in ovarian cancer receptor-related gene signature through bioinformatics analysis to construct a risk model for ovarian cancer immunotherapy: a Society for Immunotherapy of Cancer (SITC) strategic vision Structural and Molecular Senior Research Associate/Associate Scientist, Protein Science Post-Doctoral Fellow—Pharmacology/Cell Biology

October 23-25, 2024 Engage with your peers and delve into the latest developments in adhesion GPCR biology for its First-in-class GPR68 Inhibitor Asengeprast (FT011) AlphaProteo generates novel proteins for biology and health research Innovate UK announced the winners of its Transforming Cancer Therapeutics grant, which focuses on developing life-changing cancer treatments. Emerging Voices in GPCR Biology in Special Issue of Molecular Pharmacology GPCR Events, Meetings, and

Chakit Arora, J Silvio Gutkind, and Francesco Raimondi for their work on The landscape of cancer-rewired this fabulous event that brings together scientists worldwide working on all aspects of adhesion GPCR biology protein-coupled receptor 141 expressed in myeloid cells functions as an inflammation suppressor The landscape of cancer-rewired Lipid mediators in neutrophil biology: inflammation, resolution and beyond Exploring GPCR signaling pathway networks as cancer therapeutic targets Generation of comprehensive GPCR-transducer-deficient

GPCRs in Oncology and Immunology Vasoactive intestinal peptide receptor 2 signaling promotes breast cancer Progressive Technologies and Approaches Revealing Novel GPCR Biology and Drug Development Potential. GPCR Jobs Biotechnology and Biological Sciences Doctoral Training Programme Senior QM Manager Director of Molecular Pharmacology, Discovery Biology Staff Scientist/Senior Staff Scientist, Disease Biology

2024 Get ready to connect with your peers and explore the cutting-edge advancements in adhesion GPCR biology using polymer-encapsulated nanodiscs Google DeepMind And Isomorphic Labs Are Making Rapid Progress In Biology Emerging Voices in GPCR Biology in Special Issue of Molecular Pharmacology GPCR Events, Meetings, and Postdoctoral Scholar – iPSC in cardiac and endothelial cell function Protein Biochemist/Structural Biologist in a mouse model of sciatic nerve injury GPCRs in Oncology and Immunology GPR37 promotes colorectal cancer

This significant event in adhesion GPCR Biology will be held in vibrant Mexico City from October 23 to exciting event, which brings together scientists worldwide to explore all aspects of adhesion GPCR biology correlation study of adhesion G protein-coupled receptors as potential therapeutic targets for breast cancer Phosphorylation and G-Protein Mediated Signaling Networks June 25 - 29, 2024 | FENS Forum 2024 October 2024 | Biologics Senior Research Associate/Associate Scientist, Protein Science Post-Doctoral Fellow—Pharmacology/Cell Biology

in autism spectrum disorders GPCRs in Oncology and Immunology Molecular characterization of breast cancer GPCRs, and more Tri-part NanoLuc as a new split technology with potential applications in chemical biology 2023 Half Year And Second Quarter Financial Results And Provides Corporate Update Sosei Heptares and Cancer Research UK Announce the Dosing of the First Patient in a Phase I/IIa Trial with Cancer Immunotherapy

colitis GPCRs in Oncology and Immunology Polarizing itch Biochemical pharmacology of adenylyl cyclases in cancer protein-coupled receptor (GPCR) gene variants and human genetic disease Advances and challenges in cancer 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 Phosphorylation and G-Protein Mediated Signaling Networks June 25 - 29, 2024 | FENS Forum 2024 October 2024 | Biologics

passion, and interact with your exceptional peers to explore the latest advancements in adhesion GPCR biology scientists uncover “plant-like” behavior in important human cell regulator, opening up a new drug target for cancer Emerging Voices in GPCR Biology in Special Issue of Molecular Pharmacology GPCR Events, Meetings, and Postdoctoral Scholar – iPSC in cardiac and endothelial cell function Protein Biochemist/Structural Biologist spinal cord injury GPCRs in Oncology and Immunology Biochemical pharmacology of adenylyl cyclases in cancer

Mexico City 📅 October 23-25, 2024 Join us to connect with peers and explore the latest in adhesion GPCR biology Nominated for Prestigious Prix Galien USA ‘Best Startup’ Award: Pioneering GPCR-Driven Immunotherapies in Cancer Highlighting ADS024 a Novel Oral Agent for Neuroinflammation Call for GPCR Papers Emerging Voices in GPCR Biology cell-based assays in drug discovery September 30 - October 3, 2024 | 22nd Discovery on Target October 2024 | Biologics future directions Going rogue: mechanisms, regulation, and roles of mutationally activated Gα in human cancer

In various pathological conditions, including cancer, aberrant ERK activity can lead to uncontrolled ERK: a double-edged sword in cancer. ERK-dependent apoptosis as a potential therapeutic strategy for cancer. Cells, 10(10), 2509. Biology of the Cell, 93(1‐2), 71-79. Wei, H., Ahn, S., Shenoy, S. K., Karnik, S.

An antibody-drug conjugate targeting GPR56 demonstrates efficacy in preclinical models of colorectal cancer Structure pulls off rare IPO, raising $161M 3-drug combo leads to 'unprecedented' response in pancreatic cancer SLAS 2023 B Building Biology in 3D Symposium. Progressive Technologies and Approaches Revealing Novel GPCR Biology and Drug Development Potential.

Connect with fellow scientists and dive into the latest in adhesion GPCR biology. GPCRs in Oncology and Immunology Unveiling G-protein coupled receptors as potential targets for ovarian cancer to Advance a Pipeline of Novel GPCR-Modulating Therapies into Clinical Development How To Discover Biologics September 18, 2024 | FREE Webinar - The value of GPCR cell-based assays in drug discovery October 2024 | Biologics

For example, chemotherapy, a powerful standard approach to kill fast-growing cancer cells, has the drawback Modern drug development approaches include a range of techniques leveraging structural biology, immunology

and the multifunctional scaffolding protein β-arrestin2 are key integrated signaling nodes in various biological multiple roles in the pathological mechanisms of a wide range of diseases including heart failure, cancer