7s3i
Ex4-D-Ala bound to the glucagon-like peptide-1 receptor/g protein complex (conformer 2)
Structural highlights
FunctionGBG2_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction (By similarity). Publication Abstract from PubMedRecent advances in G-protein-coupled receptor (GPCR) structural elucidation have strengthened previous hypotheses that multidimensional signal propagation mediated by these receptors depends, in part, on their conformational mobility; however, the relationship between receptor function and static structures is inherently uncertain. Here, we examine the contribution of peptide agonist conformational plasticity to activation of the glucagon-like peptide 1 receptor (GLP-1R), an important clinical target. We use variants of the peptides GLP-1 and exendin-4 (Ex4) to explore the interplay between helical propensity near the agonist N terminus and the ability to bind to and activate the receptor. Cryo-EM analysis of a complex involving an Ex4 analog, the GLP-1R and G(s) heterotrimer revealed two receptor conformers with distinct modes of peptide-receptor engagement. Our functional and structural data, along with molecular dynamics (MD) simulations, suggest that receptor conformational dynamics associated with flexibility of the peptide N-terminal activation domain may be a key determinant of agonist efficacy. Structural and functional diversity among agonist-bound states of the GLP-1 receptor.,Cary BP, Deganutti G, Zhao P, Truong TT, Piper SJ, Liu X, Belousoff MJ, Danev R, Sexton PM, Wootten D, Gellman SH Nat Chem Biol. 2022 Mar;18(3):256-263. doi: 10.1038/s41589-021-00945-w. Epub 2021 , Dec 22. PMID:34937906[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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