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Title | Functional screening and rational design of compounds targeting GPR132 to treat diabetes. |
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Journal, issue, pages | Nat Metab, Vol. 5, Issue 10, Page 1726-1746, Year 2023 |
Publish date | Sep 28, 2023 |
Authors | Jia-Le Wang / Xiao-Dong Dou / Jie Cheng / Ming-Xin Gao / Guo-Feng Xu / Wei Ding / Jin-Hui Ding / Yu Li / Si-Han Wang / Zhao-Wei Ji / Xin-Yi Zhao / Tong-Yu Huo / Cai-Fang Zhang / Ya-Meng Liu / Xue-Ying Sha / Jia-Rui Gao / Wen-Hui Zhang / Yong Hao / Cheng Zhang / Jin-Peng Sun / Ning Jiao / Xiao Yu / |
PubMed Abstract | 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 ...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. |
External links | Nat Metab / PubMed:37770763 |
Methods | EM (single particle) |
Resolution | 2.95 - 3.04 Å |
Structure data | EMDB-34948, PDB-8hqe: EMDB-34950, PDB-8hqm: EMDB-34951, PDB-8hqn: EMDB-35044, PDB-8hvi: |
Chemicals | ChemComp-140: ChemComp-9HO: ChemComp-NFI: |
Source |
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Keywords | MEMBRANE PROTEIN / GPCR / GPR132 |