2. Academic Validation
  3. Activation of the GLP-1 receptor by a non-peptidic agonist

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

  • Nature. 2020 Jan;577(7790):432-436. doi: 10.1038/s41586-019-1902-z.
Peishen Zhao  # 1,  Yi-Lynn Liang  # 1,  Matthew J Belousoff  # 1,  Giuseppe Deganutti  # 2,  Madeleine M Fletcher 1,  Francis S Willard 3,  Michael G Bell 3,  Michael E Christe 3,  Kyle W Sloop 3,  Asuka Inoue 4,  Tin T Truong 1,  Lachlan Clydesdale 1,  Sebastian G B Furness 1,  Arthur Christopoulos 1,  Ming-Wei Wang 5 6,  Laurence J Miller 7,  Christopher A Reynolds 2,  Radostin Danev 8,  Patrick M Sexton 9 10,  Denise Wootten 11 12
Affiliations

Affiliations

  • 1 Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
  • 2 School of Biological Sciences, University of Essex, Colchester, UK.
  • 3 Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
  • 4 Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan.
  • 5 The National Center for Drug Screening and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 6 School of Pharmacy, Fudan University, Shanghai, China.
  • 7 Mayo Clinic, Scottsdale, AZ, USA.
  • 8 Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan. rado@m.u-tokyo.ac.jp.
  • 9 Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. patrick.sexton@monash.edu.
  • 10 School of Pharmacy, Fudan University, Shanghai, China. patrick.sexton@monash.edu.
  • 11 Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. denise.wootten@monash.edu.
  • 12 School of Pharmacy, Fudan University, Shanghai, China. denise.wootten@monash.edu.
  • # Contributed equally.
PMID: 31915381 DOI: 10.1038/s41586-019-1902-z
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.

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