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. sye@tju.edu.cn.
  • 5 Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China. sye@tju.edu.cn.
  • 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. wushan91@hubu.edu.cn.
  • 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. anna.qiao@tju.edu.cn.
  • # 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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