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, Denise Wootten

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)432-436
Number of pages5
JournalNature
Volume577
Issue number7790
DOIs
StatePublished - Jan 16 2020

Fingerprint

GTP-Binding Proteins
Peptide Receptors
G-Protein-Coupled Receptors
Detergents
Chronic Disease
Ligands
Lipids
Peptides
Glucagon-Like Peptide-1 Receptor

ASJC Scopus subject areas

  • General

Cite this

Zhao, P., Liang, Y. L., Belousoff, M. J., Deganutti, G., Fletcher, M. M., Willard, F. S., ... Wootten, D. (2020). Activation of the GLP-1 receptor by a non-peptidic agonist. Nature, 577(7790), 432-436. https://doi.org/10.1038/s41586-019-1902-z

Activation of the GLP-1 receptor by a non-peptidic agonist. / Zhao, Peishen; Liang, Yi Lynn; Belousoff, Matthew J.; Deganutti, Giuseppe; Fletcher, Madeleine M.; Willard, Francis S.; Bell, Michael G.; Christe, Michael E.; Sloop, Kyle W.; Inoue, Asuka; Truong, Tin T.; Clydesdale, Lachlan; Furness, Sebastian G.B.; Christopoulos, Arthur; Wang, Ming Wei; Miller, Laurence J.; Reynolds, Christopher A.; Danev, Radostin; Sexton, Patrick M.; Wootten, Denise.

In: Nature, Vol. 577, No. 7790, 16.01.2020, p. 432-436.

Research output: Contribution to journalArticle

Zhao, P, Liang, YL, Belousoff, MJ, Deganutti, G, Fletcher, MM, Willard, FS, Bell, MG, Christe, ME, Sloop, KW, Inoue, A, Truong, TT, Clydesdale, L, Furness, SGB, Christopoulos, A, Wang, MW, Miller, LJ, Reynolds, CA, Danev, R, Sexton, PM & Wootten, D 2020, 'Activation of the GLP-1 receptor by a non-peptidic agonist', Nature, vol. 577, no. 7790, pp. 432-436. https://doi.org/10.1038/s41586-019-1902-z
Zhao P, Liang YL, Belousoff MJ, Deganutti G, Fletcher MM, Willard FS et al. Activation of the GLP-1 receptor by a non-peptidic agonist. Nature. 2020 Jan 16;577(7790):432-436. https://doi.org/10.1038/s41586-019-1902-z
Zhao, Peishen ; Liang, Yi Lynn ; Belousoff, Matthew J. ; Deganutti, Giuseppe ; Fletcher, Madeleine M. ; Willard, Francis S. ; Bell, Michael G. ; Christe, Michael E. ; Sloop, Kyle W. ; Inoue, Asuka ; Truong, Tin T. ; Clydesdale, Lachlan ; Furness, Sebastian G.B. ; Christopoulos, Arthur ; Wang, Ming Wei ; Miller, Laurence J. ; Reynolds, Christopher A. ; Danev, Radostin ; Sexton, Patrick M. ; Wootten, Denise. / Activation of the GLP-1 receptor by a non-peptidic agonist. In: Nature. 2020 ; Vol. 577, No. 7790. pp. 432-436.
@article{4f81956abc504ccb98d7fbaf06740d32,
title = "Activation of the GLP-1 receptor by a non-peptidic agonist",
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.",
author = "Peishen Zhao and Liang, {Yi Lynn} and Belousoff, {Matthew J.} and Giuseppe Deganutti and Fletcher, {Madeleine M.} and Willard, {Francis S.} and Bell, {Michael G.} and Christe, {Michael E.} and Sloop, {Kyle W.} and Asuka Inoue and Truong, {Tin T.} and Lachlan Clydesdale and Furness, {Sebastian G.B.} and Arthur Christopoulos and Wang, {Ming Wei} and Miller, {Laurence J.} and Reynolds, {Christopher A.} and Radostin Danev and Sexton, {Patrick M.} and Denise Wootten",
year = "2020",
month = "1",
day = "16",
doi = "10.1038/s41586-019-1902-z",
language = "English (US)",
volume = "577",
pages = "432--436",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7790",

}

TY - JOUR

T1 - Activation of the GLP-1 receptor by a non-peptidic agonist

AU - Zhao, Peishen

AU - Liang, Yi Lynn

AU - Belousoff, Matthew J.

AU - Deganutti, Giuseppe

AU - Fletcher, Madeleine M.

AU - Willard, Francis S.

AU - Bell, Michael G.

AU - Christe, Michael E.

AU - Sloop, Kyle W.

AU - Inoue, Asuka

AU - Truong, Tin T.

AU - Clydesdale, Lachlan

AU - Furness, Sebastian G.B.

AU - Christopoulos, Arthur

AU - Wang, Ming Wei

AU - Miller, Laurence J.

AU - Reynolds, Christopher A.

AU - Danev, Radostin

AU - Sexton, Patrick M.

AU - Wootten, Denise

PY - 2020/1/16

Y1 - 2020/1/16

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85077614219&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85077614219&partnerID=8YFLogxK

U2 - 10.1038/s41586-019-1902-z

DO - 10.1038/s41586-019-1902-z

M3 - Article

C2 - 31915381

AN - SCOPUS:85077614219

VL - 577

SP - 432

EP - 436

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7790

ER -