6WHC

CryoEM Structure of the glucagon receptor with a dual-agonist peptide

Summary for 6WHC

• Entry DOI: 10.2210/pdb6whc/pdb
• EMDB information: 21671
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: gpcr, receptor complex, membrane protein, agonist
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 163556.64

Authors

Belousoff, M.J.,Sexton, P.,Danev, R. (deposition date: 2020-04-07, release date: 2020-05-27, Last modification date: 2025-06-04)

Primary citation

Chang, R.,Zhang, X.,Qiao, A.,Dai, A.,Belousoff, M.J.,Tan, Q.,Shao, L.,Zhong, L.,Lin, G.,Liang, Y.L.,Ma, L.,Han, S.,Yang, D.,Danev, R.,Wang, M.W.,Wootten, D.,Wu, B.,Sexton, P.M.
Cryo-electron microscopy structure of the glucagon receptor with a dual-agonist peptide.
J.Biol.Chem., 295:9313-9325, 2020

PubMed Abstract: Unimolecular dual agonists of the glucagon (GCG) receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R) are a new class of drugs that are potentially superior to GLP-1R-specific agonists for the management of metabolic disease. The dual-agonist, peptide 15 (P15), is a glutamic acid 16 analog of GCG with GLP-1 peptide substitutions between amino acids 17 and 24 that has potency equivalent to those of the cognate peptide agonists at the GCGR and GLP-1R. Here, we have used cryo-EM to solve the structure of an active P15-GCGR-G complex and compared this structure to our recently published structure of the GCGR-G complex bound to GCG. This comparison revealed that P15 has a reduced interaction with the first extracellular loop (ECL1) and the top of transmembrane segment 1 (TM1) such that there is increased mobility of the GCGR extracellular domain and at the C terminus of the peptide compared with the GCG-bound receptor. We also observed a distinct conformation of ECL3 and could infer increased mobility of the far N-terminal His-1 residue in the P15-bound structure. These regions of conformational variance in the two peptide-bound GCGR structures were also regions that were distinct between GCGR structures and previously published peptide-bound structures of the GLP-1R, suggesting that greater conformational dynamics may contribute to the increased efficacy of P15 in activation of the GLP-1R compared with GCG. The variable domains in this receptor have previously been implicated in biased agonism at the GLP-1R and could result in altered signaling of P15 at the GCGR compared with GCG.

PubMed: 32371397
DOI: 10.1074/jbc.RA120.013793

Experimental method

ELECTRON MICROSCOPY (3.4 Å)