National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM056414
オーストラリア
National Science Foundation (NSF, United States)
DGE-1747503
オーストラリア
Japan Science and Technology
18069571
オーストラリア
Australian Research Council (ARC)
IC200100052
オーストラリア
National Health and Medical Research Council (NHMRC, Australia)
1150083
オーストラリア
National Health and Medical Research Council (NHMRC, Australia)
1154434
オーストラリア
National Health and Medical Research Council (NHMRC, Australia)
1126857
オーストラリア
National Health and Medical Research Council (NHMRC, Australia)
1184726
オーストラリア
National Health and Medical Research Council (NHMRC, Australia)
1155302
オーストラリア
引用
ジャーナル: Nat Chem Biol / 年: 2022 タイトル: Structural and functional diversity among agonist-bound states of the GLP-1 receptor. 著者: Brian P Cary / Giuseppe Deganutti / Peishen Zhao / Tin T Truong / Sarah J Piper / Xinyu Liu / Matthew J Belousoff / Radostin Danev / Patrick M Sexton / Denise Wootten / Samuel H Gellman / 要旨: Recent advances in G-protein-coupled receptor (GPCR) structural elucidation have strengthened previous hypotheses that multidimensional signal propagation mediated by these receptors depends, in ...Recent 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 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.