8hqm

Activation mechanism of GPR132 by NPGLY

spinqualitylabelsall models 8hqm, resolution 2.95Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8hqm is a 5 chain structure with sequence from Escherichia coli, Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.95Å Ligands: 140 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GBB1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction. Publication Abstract from PubMed Chronic inflammation due to islet-residing macrophages plays key roles in the development of type 2 diabetes mellitus. By systematically profiling intra-islet lipid-transmembrane receptor signalling in islet-resident macrophages, we identified endogenous 9(S)-hydroxy-10,12-octadecadienoic acid-G-protein-coupled receptor 132 (GPR132)-Gi signalling as a significant contributor to islet macrophage reprogramming and found that GPR132 deficiency in macrophages reversed metabolic disorders in mice fed a high-fat diet. The cryo-electron microscopy structures of GPR132 bound with two endogenous agonists, N-palmitoylglycine and 9(S)-hydroxy-10,12-octadecadienoic acid, enabled us to rationally design both GPR132 agonists and antagonists with high potency and selectivity through stepwise translational approaches. We ultimately identified a selective GPR132 antagonist, NOX-6-18, that modulates macrophage reprogramming within pancreatic islets, decreases weight gain and enhances glucose metabolism in mice fed a high-fat diet. Our study not only illustrates that intra-islet lipid signalling contributes to islet macrophage reprogramming but also provides a broadly applicable strategy for the identification of important G-protein-coupled receptor targets in pathophysiological processes, followed by the rational design of therapeutic leads for refractory diseases such as diabetes. Functional screening and rational design of compounds targeting GPR132 to treat diabetes.,Wang JL, Dou XD, Cheng J, Gao MX, Xu GF, Ding W, Ding JH, Li Y, Wang SH, Ji ZW, Zhao XY, Huo TY, Zhang CF, Liu YM, Sha XY, Gao JR, Zhang WH, Hao Y, Zhang C, Sun JP, Jiao N, Yu X Nat Metab. 2023 Oct;5(10):1726-1746. doi: 10.1038/s42255-023-00899-4. Epub 2023 , Sep 28. PMID:37770763 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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