Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 293, Issue 24, Pages 9370-9387Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA118.003278
Keywords
G protein-coupled receptor (GPCR); glucagon; receptor structure-function; cell signaling; site-directed mutagenesis; biased agonism; GLP-1 receptor; glucagon-like peptide-1; class B peptide hormone; ERK kinase; arrestin; transmembrane domain
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Funding
- National Health and Medical Research Council of Australia [1061044, 1065410, 1126857]
- National Health and Medical Research Council [1055134]
- Shanghai Science and Technology Development Fund [15DZ2291600]
- National Natural Science Foundation of China [81573479]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDA12020347, XDA12040308]
- Chinese Academy of Sciences
- National Health and Medical Research Council of Australia [1061044, 1065410, 1126857] Funding Source: NHMRC
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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 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.
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