2. Academic Validation
  3. Activation and signaling mechanism revealed by GPR119-Gs complex structures

Activation and signaling mechanism revealed by GPR119-Gs complex structures

  • Nat Commun. 2022 Nov 17;13(1):7033. doi: 10.1038/s41467-022-34696-6.
Yuxia Qian # 1,  Jiening Wang # 2,  Linlin Yang # 3,  Yanru Liu 1,  Lina Wang 3,  Wei Liu 1,  Yun Lin 1,  Hong Yang 2,  Lixin Ma 2,  Sheng Ye 4 5,  Shan Wu 6,  Anna Qiao 7
Affiliations

Affiliations

  • 1 Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University, Tianjin, P. R. China.
  • 2 State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, School of Life Sciences, Hubei University, Wuhan, Hubei, China.
  • 3 Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.
  • 4 Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University, Tianjin, P. R. China. [email protected].
  • 5 Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China. [email protected].
  • 6 State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, School of Life Sciences, Hubei University, Wuhan, Hubei, China. [email protected].
  • 7 Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University, Tianjin, P. R. China. [email protected].
  • # Contributed equally.
PMID: 36396650 DOI: 10.1038/s41467-022-34696-6
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.

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