Conformational states of the full-length glucagon receptor

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, Clinton S. Potter, Hu Zhou, Patrick R. Griffin, Bridget Carragher, Huaiyu Yang, Ming-Wei Wang, Raymond C. Stevens and Hualiang Jiang ()
Additional contact information
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
Hualiang Jiang: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8859

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