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-Structure paper
タイトル | Activation of the GLP-1 receptor by a non-peptidic agonist. |
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ジャーナル・号・ページ | Nature, Vol. 577, Issue 7790, Page 432-436, Year 2020 |
掲載日 | 2020年1月8日 |
![]() | Peishen Zhao / Yi-Lynn Liang / Matthew J Belousoff / Giuseppe Deganutti / Madeleine M Fletcher / Francis S Willard / Michael G Bell / Michael E Christe / Kyle W Sloop / Asuka Inoue / Tin T Truong / Lachlan Clydesdale / Sebastian G B Furness / Arthur Christopoulos / Ming-Wei Wang / Laurence J Miller / Christopher A Reynolds / Radostin Danev / Patrick M Sexton / Denise Wootten / ![]() ![]() ![]() ![]() ![]() |
PubMed 要旨 | Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, including diabetes and obesity. Structures of active receptors reveal peptide agonists engage deep within ...Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, including diabetes and obesity. Structures of active receptors reveal peptide agonists engage deep within the receptor core, leading to an outward movement of extracellular loop 3 and the tops of transmembrane helices 6 and 7, an inward movement of transmembrane helix 1, reorganization of extracellular loop 2 and outward movement of the intracellular side of transmembrane helix 6, resulting in G-protein interaction and activation. Here we solved the structure of a non-peptide agonist, TT-OAD2, bound to the glucagon-like peptide-1 (GLP-1) receptor. Our structure identified an unpredicted non-peptide agonist-binding pocket in which reorganization of extracellular loop 3 and transmembrane helices 6 and 7 manifests independently of direct ligand interaction within the deep transmembrane domain pocket. TT-OAD2 exhibits biased agonism, and kinetics of G-protein activation and signalling that are distinct from peptide agonists. Within the structure, TT-OAD2 protrudes beyond the receptor core to interact with the lipid or detergent, providing an explanation for the distinct activation kinetics that may contribute to the clinical efficacy of this compound series. This work alters our understanding of the events that drive the activation of class B receptors. |
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手法 | EM (単粒子) |
解像度 | 3.0 Å |
構造データ | EMDB-20179, PDB-6orv: |
化合物 | ![]() ChemComp-N2V: |
由来 |
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![]() | MEMBRANE PROTEIN / G-coupled protein receptor / GPCR / non-peptide angonist |