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Structure of the full-length glucagon class B G-protein-coupled receptor

Author

Listed:
  • Haonan Zhang

    (CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Anna Qiao

    (CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Dehua Yang

    (CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences)

  • Linlin Yang

    (School of Basic Medical Sciences, Zhengzhou University)

  • Antao Dai

    (CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences)

  • Chris de Graaf

    (Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam)

  • Steffen Reedtz-Runge

    (Novo Nordisk A/S, Novo Nordisk Park)

  • Venkatasubramanian Dharmarajan

    (The Scripps Research Institute)

  • Hui Zhang

    (CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Gye Won Han

    (Bridge Institute, University of Southern California)

  • Thomas D. Grant

    (Hauptman–Woodward Institute, SUNY at Buffalo)

  • Raymond G. Sierra

    (Linac Coherent Light Source (LCLS), SLAC National Accelerator Laboratory)

  • Uwe Weierstall

    (Arizona State University)

  • Garrett Nelson

    (Arizona State University)

  • Wei Liu

    (Biodesign Center for Applied Structural Discovery, Biodesign Institute, School of Molecular Sciences, Arizona State University)

  • Yanhong Wu

    (CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    School of Life Science and Technology, ShanghaiTech University)

  • Limin Ma

    (CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences)

  • Xiaoqing Cai

    (CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences)

  • Guangyao Lin

    (CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    School of Life Science and Technology, ShanghaiTech University)

  • Xiaoai Wu

    (Novo Nordisk Research Centre China)

  • Zhi Geng

    (Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences)

  • Yuhui Dong

    (Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences)

  • Gaojie Song

    (iHuman Institute, ShanghaiTech University)

  • Patrick R. Griffin

    (The Scripps Research Institute)

  • Jesper Lau

    (Novo Nordisk A/S, Novo Nordisk Park)

  • Vadim Cherezov

    (Bridge Institute, University of Southern California)

  • Huaiyu Yang

    (Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences)

  • Michael A. Hanson

    (GPCR Consortium)

  • Raymond C. Stevens

    (School of Life Science and Technology, ShanghaiTech University
    iHuman Institute, ShanghaiTech University)

  • Qiang Zhao

    (CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences)

  • Hualiang Jiang

    (CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences)

  • Ming-Wei Wang

    (CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    School of Life Science and Technology, ShanghaiTech University
    School of Pharmacy, Fudan University)

  • Beili Wu

    (CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    School of Life Science and Technology, ShanghaiTech University
    CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences)

Abstract

The human glucagon receptor, GCGR, belongs to the class B G-protein-coupled receptor family and plays a key role in glucose homeostasis and the pathophysiology of type 2 diabetes. Here we report the 3.0 Å crystal structure of full-length GCGR containing both the extracellular domain and transmembrane domain in an inactive conformation. The two domains are connected by a 12-residue segment termed the stalk, which adopts a β-strand conformation, instead of forming an α-helix as observed in the previously solved structure of the GCGR transmembrane domain. The first extracellular loop exhibits a β-hairpin conformation and interacts with the stalk to form a compact β-sheet structure. Hydrogen–deuterium exchange, disulfide crosslinking and molecular dynamics studies suggest that the stalk and the first extracellular loop have critical roles in modulating peptide ligand binding and receptor activation. These insights into the full-length GCGR structure deepen our understanding of the signalling mechanisms of class B G-protein-coupled receptors.

Suggested Citation

  • Haonan Zhang & Anna Qiao & Dehua Yang & Linlin Yang & Antao Dai & Chris de Graaf & Steffen Reedtz-Runge & Venkatasubramanian Dharmarajan & Hui Zhang & Gye Won Han & Thomas D. Grant & Raymond G. Sierra, 2017. "Structure of the full-length glucagon class B G-protein-coupled receptor," Nature, Nature, vol. 546(7657), pages 259-264, June.
    • Handle: RePEc:nat:nature:v:546:y:2017:i:7657:d:10.1038_nature22363
    DOI: 10.1038/nature22363
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    Cited by:

    1. Fenghui Zhao & Qingtong Zhou & Zhaotong Cong & Kaini Hang & Xinyu Zou & Chao Zhang & Yan Chen & Antao Dai & Anyi Liang & Qianqian Ming & Mu Wang & Li-Nan Chen & Peiyu Xu & Rulve Chang & Wenbo Feng & T, 2022. "Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Xiuwen Zhai & Chunyou Mao & Qingya Shen & Shaokun Zang & Dan-Dan Shen & Huibing Zhang & Zhaohong Chen & Gang Wang & Changming Zhang & Yan Zhang & Zhihong Liu, 2022. "Molecular insights into the distinct signaling duration for the peptide-induced PTH1R activation," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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