biostudies-literatureYang LNCRR NIH HHSNIGMS NIH HHS7859https://www.ebi.ac.uk/biostudies/studies/S-EPMC4532856biostudies-literatureUnknown6Class 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.Nature communicationsConformational states of the full-length glucagon receptor.PMC4532856S10 RR027270U54 GM094618P41 GM103310Yang Hde Graaf CReedtz-Runge SYang LCarragher BWang CWang MWJiang HGriffin PRWu BPotter CSMoeller ASiu FYYang DSong GDharmarajan VPascal BDWest GMZhou HStevens RCfalseConformational states of the full-length glucagon receptor.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.2015-01-01T00:00:00Z2015 Jul2024-11-12T15:03:35.472Z2019-03-27T01:56:38ZS-EPMC45328562622779810.1038/ncomms8859