期刊
NATURE
卷 553, 期 7686, 页码 106-+出版社
NATURE PORTFOLIO
DOI: 10.1038/nature25153
关键词
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资金
- CAS Strategic Priority Research Program [XDB08020000]
- CAS [QYZDB-SSW-SMC024, QYZDB-SSW-SMC054]
- National Science Foundation of China [31422017, 81525024]
- Shanghai Science and Technology Development Fund [15DZ2291600]
- E-Institutes of Shanghai Municipal Education Commission [E09013]
- Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund [U1501501]
- Canada Excellence Research Chairs program
- Canadian Institute for Advanced Research
Class B G-protein-coupled receptors (GPCRs), which consist of an extracellular domain (ECD) and a transmembrane domain (TMD), respond to secretin peptides to play a key part in hormonal homeostasis, and are important therapeutic targets for a variety of diseases(1-8). Previous work(9-11) has suggested that peptide ligands bind to class B GPCRs according to a two-domain binding model, in which the C-terminal region of the peptide targets the ECD and the N-terminal region of the peptide binds to the TMD binding pocket. Recently, three structures of class B GPCRs in complex with peptide ligands have been solved(12-14). These structures provide essential insights into peptide ligand recognition by class B GPCRs. However, owing to resolution limitations, the specific molecular interactions for peptide binding to class B GPCRs remain ambiguous. Moreover, these previously solved structures have different ECD conformations relative to the TMD, which introduces questions regarding inter-domain conformational flexibility and the changes required for receptor activation. Here we report the 3.0 angstrom-resolution crystal structure of the full-length human glucagon receptor (GCGR) in complex with a glucagon analogue and partial agonist, NNC1702. This structure provides molecular details of the interactions between GCGR and the peptide ligand. It reveals a marked change in the relative orientation between the ECD and TMD of GCGR compared to the previously solved structure of the inactive GCGR-NNC0640-mAb1 complex. Notably, the stalk region and the first extracellular loop undergo major conformational changes in secondary structure during peptide binding, forming key interactions with the peptide. We further propose a dual-binding-site trigger model for GCGR activation-which requires conformational changes of the stalk, first extracellular loop and TMD-that extends our understanding of the previously established two-domain peptide-binding model of class B GPCRs.
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