Two distinct domains of the glucagon-like peptide-1 receptor control peptide-mediated biased agonism.

ABSTRACT: G protein-coupled receptors (GPCRs) can be differentially activated by ligands to generate multiple and distinct downstream signaling profiles, a phenomenon termed biased agonism. The glucagon-like peptide-1 receptor (GLP-1R) is a class B GPCR and a key drug target for managing metabolic disorders; however, its peptide agonists display biased signaling that affects their relative efficacies. In this study, we combined mutagenesis experiments and mapping of surface mutations onto recently described GLP-1R structures, which revealed two major domains in the GLP-1/GLP-1R/G_s protein active structure that are differentially important for both receptor quiescence and ligand-specific initiation and propagation of biased agonism. Changes to the conformation of transmembrane helix (TM) 5

SUBMITTER: Lei S 

PROVIDER: S-EPMC6005446 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature