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TitleFunctional screening and rational design of compounds targeting GPR132 to treat diabetes.
Journal, issue, pagesNat Metab, Vol. 5, Issue 10, Page 1726-1746, Year 2023
Publish dateSep 28, 2023
AuthorsJia-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 AbstractChronic 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 linksNat Metab / PubMed:37770763
MethodsEM (single particle)
Resolution2.95 - 3.04 Å
Structure data

34948

8hqe

EMDB-34948, PDB-8hqe:
Cryo-EM structure of the apo-GPR132-Gi
Method: EM (single particle) / Resolution: 2.97 Å

34950

8hqm

EMDB-34950, PDB-8hqm:
Activation mechanism of GPR132 by NPGLY
Method: EM (single particle) / Resolution: 2.95 Å

34951

8hqn

EMDB-34951, PDB-8hqn:
Activation mechanism of GPR132 by 9(S)-HODE
Method: EM (single particle) / Resolution: 3.0 Å

35044

8hvi

EMDB-35044, PDB-8hvi:
Activation mechanism of GPR132 by compound NOX-6-7
Method: EM (single particle) / Resolution: 3.04 Å

Chemicals

ChemComp-140:
N-PALMITOYLGLYCINE

ChemComp-9HO:
(9S,10E,12Z)-9-hydroxyoctadeca-10,12-dienoic acid / 9-Hydroxyoctadecadienoic acid

ChemComp-NFI:
3-methyl-5-[(4-oxidanylidene-4-phenyl-butanoyl)amino]-1-benzofuran-2-carboxylic acid

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
  • escherichia coli (E. coli)
KeywordsMEMBRANE PROTEIN / GPCR / GPR132

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