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Activation of the GLP-1 receptor by a non-peptidic agonist

Zhao, Peishen and Liang, Yi-Lynn and Belousoff, Matthew J and Deganutti, Giuseppe and Fletcher, Madeleine M and Willard, Francis S and Bell, Michael G and Christe, Michael E and Sloop, Kyle W and Inoue, Asuka and Truong, Tin T and Clydesdale, Lachlan and Furness, Sebastian GB and Christopoulos, Arthur and Wang, Ming-Wei and Miller, Laurence J and Reynolds, Christopher A and Danev, Radostin and Sexton, Patrick M and Wootten, Denise (2020) 'Activation of the GLP-1 receptor by a non-peptidic agonist.' Nature, 577 (7790). 432 - 436. ISSN 0028-0836

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TT_OAD2 final Revision 121019.pdf - Accepted Version

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Abstract

Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, including diabetes and obesity1. 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 activation2,3,4,5,6. 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.

Item Type: Article
Divisions: Faculty of Science and Health > Life Sciences, School of
Depositing User: Elements
Date Deposited: 23 Jan 2020 10:03
Last Modified: 19 Aug 2020 15:10
URI: http://repository.essex.ac.uk/id/eprint/26541

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