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 diseases1,2,3,4,5,6,7,8. Previous work9,10,11 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 solved12,13,14. 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 Å-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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This work was supported by CAS Strategic Priority Research Program XDB08020000, CAS grants QYZDB-SSW-SMC024 (B.W.) and QYZDB-SSW-SMC054 (Q.Z.), the National Science Foundation of China grants 31422017 (B.W.) and 81525024 (Q.Z.), the Shanghai Science and Technology Development Fund 15DZ2291600 (M.-W.W.), the E-Institutes of Shanghai Municipal Education Commission (E09013), the Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (second phase) under Grant No. U1501501, and the Canada Excellence Research Chairs program and the Canadian Institute for Advanced Research (O.P.E.). O.P.E. holds the Anne and Max Tanenbaum Chair in Neuroscience. We also thank the computer centre of East China Normal University for computational resources. The synchrotron radiation experiments were performed at the BL41XU of SPring-8 with the approval of the Japan Synchrotron Radiation Research Institute (proposal numbers 2016B2517, 2016B2518, 2017A2505 and 2017A2506). We thank the beamline staff members K. Hasegawa, N. Mizuno, T. Kawamura and H. Murakami of the BL41XU for help with X-ray data collection.
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Journal of Molecular Neuroscience (2018)