Journal
NATURE
Volume 546, Issue 7657, Pages 259-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature22363
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Funding
- National Basic Research Program of China [2014CB910400, 2015CB910304]
- CAS Strategic Priority Research Program [XDB08020000]
- CAS [QYZDB-SSW-SMC024]
- National Science Foundation of China [31422017, 81525024, 81230076, 81573479]
- National Health and Family Planning Commission [2012ZX09304-011, 2013ZX09401003-005, 2013ZX09507001, 2013ZX09507-002]
- Shanghai Science and Technology Development Fund [15DZ2291600]
- National Institutes of Health [R01 GM108635, R21 DA042298, P41GM103393]
- National Science Foundation STC award [1231306]
- GPCR Consortium
- Shanghai local government
- Netherlands eScience Center (NLeSC)/NWO (Enabling Technologies project: 3D-e-Chem) [027.014.201]
- US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
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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 angstrom 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 beta-strand conformation, instead of forming an alpha-helix as observed in the previously solved structure of the GCGR transmembrane domain. The first extracellular loop exhibits a beta-hairpin conformation and interacts with the stalk to form a compact beta-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.
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