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Activation and signaling mechanism revealed by GPR119-Gs complex structures

Author

Listed:
  • 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
    Zhejiang University)

  • Shan Wu

    (Hubei University)

  • Anna Qiao

    (Tianjin University)

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.

Suggested Citation

  • Yuxia Qian & Jiening Wang & Linlin Yang & Yanru Liu & Lina Wang & Wei Liu & Yun Lin & Hong Yang & Lixin Ma & Sheng Ye & Shan Wu & Anna Qiao, 2022. "Activation and signaling mechanism revealed by GPR119-Gs complex structures," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34696-6
    DOI: 10.1038/s41467-022-34696-6
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