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- W4221119792 abstract "The glucagon-like peptide-1 receptor (GLP-1R) has broad physiological roles and is a validated target for treatment of metabolic disorders. Despite recent advances in GLP-1R structure elucidation, detailed mechanistic understanding of how different peptides generate profound differences in G protein-mediated signalling is still lacking. Here we combine cryo-electron microscopy, molecular dynamics simulations, receptor mutagenesis and pharmacological assays, to interrogate the mechanism and consequences of GLP-1R binding to four peptide agonists; glucagon-like peptide-1, oxyntomodulin, exendin-4 and exendin-P5. These data reveal that distinctions in peptide N-terminal interactions and dynamics with the GLP-1R transmembrane domain are reciprocally associated with differences in the allosteric coupling to G proteins. In particular, transient interactions with residues at the base of the binding cavity correlate with enhanced kinetics for G protein activation, providing a rationale for differences in G protein-mediated signalling efficacy from distinct agonists." @default.
- W4221119792 created "2022-04-03" @default.
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- W4221119792 date "2022-01-10" @default.
- W4221119792 modified "2023-10-15" @default.
- W4221119792 title "Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation" @default.
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- W4221119792 doi "https://doi.org/10.1038/s41467-021-27760-0" @default.
- W4221119792 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/35013280" @default.
- W4221119792 hasPublicationYear "2022" @default.
- W4221119792 type Work @default.