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Cryo-EM structure of an activated VIP1 receptor-G protein complex revealed by a NanoBiT tethering strategy

Author

Listed:
  • Jia Duan

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Dan-dan Shen

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine)

  • X. Edward Zhou

    (Van Andel Institute)

  • Peng Bi

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine)

  • Qiu-feng Liu

    (Chinese Academy of Sciences)

  • Yang-xia Tan

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    ShanghaiTech University)

  • You-wen Zhuang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Hui-bing Zhang

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine)

  • Pei-yu Xu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Si-Jie Huang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    ShanghaiTech University)

  • Shan-shan Ma

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Xin-heng He

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Karsten Melcher

    (Van Andel Institute)

  • Yan Zhang

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine)

  • H. Eric Xu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    ShanghaiTech University)

  • Yi Jiang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

Abstract

Vasoactive intestinal polypeptide receptor (VIP1R) is a widely expressed class B G protein-coupled receptor and a drug target for the treatment of neuronal, metabolic, and inflammatory diseases. However, our understanding of its mechanism of action and the potential of drug discovery targeting this receptor is limited by the lack of structural information of VIP1R. Here we report a cryo-electron microscopy structure of human VIP1R bound to PACAP27 and Gs heterotrimer, whose complex assembly is stabilized by a NanoBiT tethering strategy. Comparison with other class B GPCR structures reveals that PACAP27 engages VIP1R with its N-terminus inserting into the ligand binding pocket at the transmembrane bundle of the receptor, which subsequently couples to the G protein in a receptor-specific manner. This structure has provided insights into the molecular basis of PACAP27 binding and VIP receptor activation. The methodology of the NanoBiT tethering may help to provide structural information of unstable complexes.

Suggested Citation

  • Jia Duan & Dan-dan Shen & X. Edward Zhou & Peng Bi & Qiu-feng Liu & Yang-xia Tan & You-wen Zhuang & Hui-bing Zhang & Pei-yu Xu & Si-Jie Huang & Shan-shan Ma & Xin-heng He & Karsten Melcher & Yan Zhang, 2020. "Cryo-EM structure of an activated VIP1 receptor-G protein complex revealed by a NanoBiT tethering strategy," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17933-8
    DOI: 10.1038/s41467-020-17933-8
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