5YQZ

Structure of the glucagon receptor in complex with a glucagon analogue

Summary for 5YQZ

• Entry DOI: 10.2210/pdb5yqz/pdb
• Descriptor: Glucagon receptor,Endolysin,Glucagon receptor, Glucagon analogue, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: human gcgr receptor, class b, 7tm domain, membrane, lcp, xfel, signaling protein, signaling protein-hydrolase complex, signaling protein/hydrolase
• Biological source: Homo sapiens (Human); More
• Cellular location: Cell membrane ; Multi-pass membrane protein : P47871
• Total number of polymer chains: 2
• Total formula weight: 72227.75

Authors

Zhang, H.,Qiao, A.,Yang, L.,VAN EPS, N.,Frederiksen, K.,Yang, D.,Dai, A.,Cai, X.,Zhang, H.,Yi, C.,Can, C.,He, L.,Yang, H.,Lau, J.,Ernst, O.,Hanson, M.,Stevens, R.,Wang, M.,Seedtz-Runge, S.,Jiang, H.,Zhao, Q.,Wu, B. (deposition date: 2017-11-08, release date: 2018-01-17, Last modification date: 2024-11-20)

Primary citation

Zhang, H.,Qiao, A.,Yang, L.,Van Eps, N.,Frederiksen, K.S.,Yang, D.,Dai, A.,Cai, X.,Zhang, H.,Yi, C.,Cao, C.,He, L.,Yang, H.,Lau, J.,Ernst, O.P.,Hanson, M.A.,Stevens, R.C.,Wang, M.W.,Reedtz-Runge, S.,Jiang, H.,Zhao, Q.,Wu, B.
Structure of the glucagon receptor in complex with a glucagon analogue.
Nature, 553:106-110, 2018

PubMed Abstract: 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. Previous work 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. 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.

PubMed: 29300013
DOI: 10.1038/nature25153

Experimental method

X-RAY DIFFRACTION (3 Å)