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

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 () and Denise Wootten ()
Additional contact information
Peishen Zhao: Monash University
Yi-Lynn Liang: Monash University
Matthew J. Belousoff: Monash University
Giuseppe Deganutti: University of Essex
Madeleine M. Fletcher: Monash University
Francis S. Willard: Eli Lilly and Company
Michael G. Bell: Eli Lilly and Company
Michael E. Christe: Eli Lilly and Company
Kyle W. Sloop: Eli Lilly and Company
Asuka Inoue: Tohoku University
Tin T. Truong: Monash University
Lachlan Clydesdale: Monash University
Sebastian G. B. Furness: Monash University
Arthur Christopoulos: Monash University
Ming-Wei Wang: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Laurence J. Miller: Mayo Clinic
Christopher A. Reynolds: University of Essex
Radostin Danev: University of Tokyo, Hongo, Bunkyo-ku
Patrick M. Sexton: Monash University
Denise Wootten: Monash University

Nature, 2020, vol. 577, issue 7790, 432-436

Abstract: 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 activation2–6. 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.

Date: 2020
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DOI: 10.1038/s41586-019-1902-z

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