Cryo-electron microscopy structure of the glucagon receptor with a dual-agonist peptide
Rulue Chang, Xin Zhang, Anna Qiao, Antao Dai, Matthew J. Belousoff, Qiuxiang Tan, Lijun Shao, Zhong‐Guang Li, Guangyao Lin, Yi-Lynn Liang, Limin Ma, Shuo Han, Dehua Yang, Radostin Danev, Ming-Wei Wang, Denise Wootten, Beili Wu, Patrick M. Sexton
Abstract
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.