Journal
NATURE COMMUNICATIONS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms8859
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Funding
- Ministry of Science and Technology of China [2012CB518005, 2012AA020302, 2013ZX09507001]
- National Natural Science Foundation of China [21422208, 81230076, 91313000, 21210003]
- National Health and Family Planning Commission of China [2013ZX09507001, 2012ZX09304-011, 2013ZX09401003-005, 2013ZX09507-002]
- Shanghai Science and Technology Development Fund [13DZ2290300, 15DZ2291600]
- National Institutes of Health [U54 GM094618]
- SA-SIBS Scholarship Program
- Thousand Talents Program in China
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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.
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