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Nat Commun. 2015 Jul 31;6:7859. doi: 10.1038/ncomms8859.

Conformational states of the full-length glucagon receptor.

Author information

1
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China.
2
The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Shanghai 201203, China.
3
Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, De Boelelaan 1083, Amsterdam 1081 HV, The Netherlands.
4
The National Resource for Automated Molecular Microscopy, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, USA.
5
Department of Molecular Therapeutics, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, USA.
6
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, USA.
7
iHuman Institute, ShanghaiTech University, 99 Haike Road, Pudong, Shanghai 201203, China.
8
Department of Modeling and Structural Biology, Novo Nordisk, Novo Nordisk Park, Malov 2760, Denmark.
9
The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
10
1] Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, USA [2] iHuman Institute, ShanghaiTech University, 99 Haike Road, Pudong, Shanghai 201203, China [3] Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, 3430 S. Vermont Avenue, Los Angeles, California 90089, USA.

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.

PMID:
26227798
PMCID:
PMC4532856
DOI:
10.1038/ncomms8859
[Indexed for MEDLINE]
Free PMC Article

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