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Two distinct domains of the glucagon-like peptide-1 receptor control peptide-mediated biased agonism
- Source :
- Journal of Biological Chemistry. 293:9370-9387
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
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 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.
- Subjects :
- Models, Molecular
0301 basic medicine
Cell signaling
Protein Conformation
CHO Cells
Crystallography, X-Ray
Ligands
Biochemistry
Glucagon-Like Peptide-1 Receptor
03 medical and health sciences
Cricetulus
Protein Domains
Drug Discovery
Cyclic AMP
Arrestin
Functional selectivity
Animals
Humans
Phosphorylation
Extracellular Signal-Regulated MAP Kinases
Receptor
Molecular Biology
Glucagon-like peptide 1 receptor
G protein-coupled receptor
Chemistry
Cell Biology
Cell biology
Transmembrane domain
030104 developmental biology
Mutagenesis
Calcium
Signal transduction
Peptides
Signal Transduction
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 293
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....ea86def2c857d6c6375b5a9acf9bec76