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September 2022 Structure of the human galanin receptor 2 bound to galanin and Gq reveals the basis of To understand the basis of the ligand preferences of the receptors and to assist structure-based drug design, we used cryo-electron microscopy (cryo-EM) to solve the molecular structure of GALR2 bound to Mutant proteins were assayed to help reveal the basis of ligand specificity, and structural comparison

We have combined recently published cryo-electron tomography (cryo-ET) data on the ROS with structural

HDX-MS-optimized approach to characterize nanobodies as tools for biochemical and structural studies single-chain camelid nanobodies using hydrogen-deuterium exchange (HDX) mass spectrometry (MS) for structural

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

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

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

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

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

Allosteric Modulator Discovery: From Serendipity to Structure-Based Design. Structure. 2019;27(4):566-578. 24.         Changeux J-P, Christopoulos A. Nature chemical biology. 2020;16(8):841-849. 44.         Cryo-EM structures of GPCRs coupled to Gs, Gi and Go. Structural insights into G protein activation by D1 dopamine receptor.

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

Therefore, it is imperative to understand the precise molecular mechanism of H2R biology.

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

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

GPCR modulators for rare diseases "29/06/2022 Confo Therapeutics, founded in 2015 as a spin-off from VIB and VUB, announced today that it has been awarded a €1.7 million grant from the Flemish Agency for Innovation

binding by searching large-scale motions accompanied with stable maintenance of the fragile cell-membrane structure

previous phase III clinical candidate for the treatment of Crohn's disease, we developed a chemical biology

that causes the Gα subunit to open, releasing GDP, and forming the experimentally observed activated structure

August 2022 Dopamine D 1 receptor-mediated β-arrestin signaling: Insight from pharmacology, biology,

., of the University of Oxford, has joined Exscientia as Chief Scientist of Biologics AI. focus on the application of artificial intelligence (AI), machine learning, and the design of protein structures She has held numerous senior roles at the University of Oxford, where she is currently Professor of Structural

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 Structural characterization of biologics, such as vaccines, viral vectors, and gene therapy agents, has

October 2022 Mechanism of enhanced sensitivity of mutated β-adrenergic-like octopamine receptor to amitraz in honeybee Apis mellifera: An insight from MD simulations "Background: Amitraz is one of the critical acaricides/insecticides for effective control of pest infestation of Varroa destructor mite, a devastating parasite of Apis mellifera, because of its low toxicity to honeybees. Previous assays verified that a typical G protein-coupled receptor, β-adrenergic-like octopamine receptor (Octβ2R), is the unique target of amitraz, but the honeybee Octβ2R resists to amitraz. However, the underlying molecular mechanism of the enhanced sensitivity or toxicity of amitraz to mutated honeybee Octβ2RE208V/I335T/I350V is not fully understood. Here, molecular dynamics simulations are employed to explore the implied mechanism of the enhanced sensitivity to amitraz in mutant honeybee Octβ2R." 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

transducer of the hedgehog (HH) morphogen, which plays an essential role in the patterning of epithelial structures

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

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

April 2022 Ono Enters into Collaboration Agreement with Domain Therapeutics and Université de Montréal