Activation and signaling mechanism revealed by GPR119-Gs complex structures

Yuxia Qian, Jiening Wang, Linlin Yang, Yanru Liu, Lina Wang, Wei Liu, Yun Lin, Hong Yang, Lixin Ma, Sheng Ye (), Shan Wu () and Anna Qiao ()
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Yuxia Qian: Tianjin University
Jiening Wang: Hubei University
Linlin Yang: Zhengzhou University
Yanru Liu: Tianjin University
Lina Wang: Zhengzhou University
Wei Liu: Tianjin University
Yun Lin: Tianjin University
Hong Yang: Hubei University
Lixin Ma: Hubei University
Sheng Ye: Tianjin University
Shan Wu: Hubei University
Anna Qiao: Tianjin University

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: Abstract 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-Gs 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 Gβs. Disruption of the salt bridge eliminates the cAMP production of GPR119, indicating an important role of Gβs 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.

Date: 2022
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DOI: 10.1038/s41467-022-34696-6

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