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Conformational states of the full-length glucagon receptor

Author

Listed:
  • Linlin Yang

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

  • Dehua Yang

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

  • Chris de Graaf

    (Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam)

  • Arne Moeller

    (The National Resource for Automated Molecular Microscopy, The Scripps Research Institute)

  • Graham M. West

    (The Scripps Research Institute)

  • Venkatasubramanian Dharmarajan

    (The Scripps Research Institute)

  • Chong Wang

    (The Scripps Research Institute)

  • Fai Y. Siu

    (The Scripps Research Institute)

  • Gaojie Song

    (iHuman Institute, ShanghaiTech University)

  • Steffen Reedtz-Runge

    (Novo Nordisk)

  • Bruce D. Pascal

    (The Scripps Research Institute)

  • Beili Wu

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

  • Clinton S. Potter

    (The National Resource for Automated Molecular Microscopy, The Scripps Research Institute)

  • Hu Zhou

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

  • Patrick R. Griffin

    (The Scripps Research Institute)

  • Bridget Carragher

    (The National Resource for Automated Molecular Microscopy, The Scripps Research Institute)

  • Huaiyu Yang

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

  • Ming-Wei Wang

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

  • Raymond C. Stevens

    (The Scripps Research Institute
    iHuman Institute, ShanghaiTech University
    Bridge Institute, University of Southern California)

  • Hualiang Jiang

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

Abstract

Class B G protein-coupled receptors are composed of an extracellular domain (ECD) and a seven-transmembrane (7TM) domain, and their signalling is regulated by peptide hormones. Using a hybrid structural biology approach together with the ECD and 7TM domain crystal structures of the glucagon receptor (GCGR), we examine the relationship between full-length receptor conformation and peptide ligand binding. Molecular dynamics (MD) and disulfide crosslinking studies suggest that apo-GCGR can adopt both an open and closed conformation associated with extensive contacts between the ECD and 7TM domain. The electron microscopy (EM) map of the full-length GCGR shows how a monoclonal antibody stabilizes the ECD and 7TM domain in an elongated conformation. Hydrogen/deuterium exchange (HDX) studies and MD simulations indicate that an open conformation is also stabilized by peptide ligand binding. The combined studies reveal the open/closed states of GCGR and suggest that glucagon binds to GCGR by a conformational selection mechanism.

Suggested Citation

  • Linlin Yang & Dehua Yang & Chris de Graaf & Arne Moeller & Graham M. West & Venkatasubramanian Dharmarajan & Chong Wang & Fai Y. Siu & Gaojie Song & Steffen Reedtz-Runge & Bruce D. Pascal & Beili Wu &, 2015. "Conformational states of the full-length glucagon receptor," Nature Communications, Nature, vol. 6(1), pages 1-13, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8859
    DOI: 10.1038/ncomms8859
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