期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-34696-6
关键词
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资金
- Ministry of Science and Technology [2020YFA0908500, 2020YFA0908400]
- National Natural Science Foundation of China [31971127, 32000851, 31900895, 31900930]
- China Postdoctoral Science Foundation [2020M672434]
- Fundamental Research Funds for the Central Universities
This study reveals that GPR119 adopts a non-canonical consensus structural scaffold and possesses an extended ligand-binding pocket for chemically different agonists.
Agonists selectively targeting cannabinoid receptor-like G-protein-coupled receptor (GPCR) GPR119 hold promise for treating metabolic disorders while avoiding unwanted side effects. Here we present the cryo-electron microscopy (cryo-EM) structures of the human GPR119-G(s) signaling complexes bound to AR231453 and MBX-2982, two representative agonists reported for GPR119. The structures reveal a one-amino acid shift of the conserved proline residue of TM5 that forms an outward bulge, opening up a hydrophobic cavity between TM4 and TM5 at the middle of the membrane for its endogenous ligands-monounsaturated lipid metabolites. In addition, we observed a salt bridge between ICL1 of GPR119 and G beta(s). Disruption of the salt bridge eliminates the cAMP production of GPR119, indicating an important role of G beta(s) in GPR119-mediated signaling. Our structures, together with mutagenesis studies, illustrate the conserved binding mode of the chemically different agonists, and provide insights into the conformational changes in receptor activation and G protein coupling. Agonists selectively targeting GPR119 hold promise for treating metabolic disorders. Here, authors reveal that GPR119 adopts a non-canonical consensus structural scaffold with an extended ligand-binding pocket for chemically different agonists.
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