Cryo-electron microscopy structure of the glucagon receptor with a dual-agonist peptide.

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_s complex and compared this structure to our recently published structure of the GCGR-G_s complex bound to GCG. This comparison revealed that P15 has a reduced interaction with the first extracellular loop (ECL1) and the top of transmembrane s

SUBMITTER: Chang R 

PROVIDER: S-EPMC7363120 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature