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-Structure paper
タイトル | Structural and functional diversity among agonist-bound states of the GLP-1 receptor. |
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ジャーナル・号・ページ | Nat Chem Biol, Vol. 18, Issue 3, Page 256-263, Year 2022 |
掲載日 | 2021年12月22日 |
![]() | 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 / ![]() ![]() ![]() ![]() |
PubMed 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. |
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手法 | EM (単粒子) |
解像度 | 2.41 - 2.51 Å |
構造データ | EMDB-24805, PDB-7s1m: EMDB-24825, PDB-7s3i: |
由来 |
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![]() | MEMBRANE PROTEIN / glucagon / GLP-1 / exendin / G protein / GDP / GTP / complex / agonist / D-alanine / D-Ala / GLP-1R |