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

Saifei Lei, Lachlan Clydesdale, Antao Dai, Xiaoqing Cai, Feng Yang, Dehua Yang, Yi-Lynn Liang, Cassandra Koole, Peishen Zhao, Thomas Coudrat, Arthur Christopoulos, Ming-Wei Wang, Denise Wootten, Patrick M Sexton

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30 Citations (Scopus)


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/Gs 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 and TM 6 and reordering of extracellular loop 2 were essential for the propagation of signaling linked to cAMP formation and intracellular calcium mobilization, whereas ordering and packing of residues in TMs 1 and 7 were critical for extracellular signal?regulated kinase 1/2 (pERK) activity. On the basis of these findings, we propose a model of distinct peptide?receptor interactions that selectively control how these different signaling pathways are engaged. This work provides important structural insight into class B GPCR activation and biased agonism.

Original languageEnglish
Pages (from-to)9370-9387
Number of pages18
JournalJournal of Biological Chemistry
Issue number24
Publication statusPublished - 1 Jan 2018

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