Differential GLP-1R Binding and Activation by Peptide and Non-peptide Agonists

  • Mol Cell. 2020 Nov 5;80(3):485-500.e7. doi: 10.1016/j.molcel.2020.09.020.
Xin Zhang  1 ,  Matthew J Belousoff  1 ,  Peishen Zhao  1 ,  Albert J Kooistra  2 ,  Tin T Truong  1 ,  Sheng Yu Ang  1 ,  Christina Rye Underwood  3 ,  Thomas Egebjerg  3 ,  Petr Šenel  4 ,  Gregory D Stewart  1 ,  Yi-Lynn Liang  1 ,  Alisa Glukhova  1 ,  Hari Venugopal  5 ,  Arthur Christopoulos  1 ,  Sebastian G B Furness  1 ,  Laurence J Miller  6 ,  Steffen Reedtz-Runge  3 ,  Christopher J Langmead  1 ,  David E Gloriam  2 ,  Radostin Danev  7 ,  Patrick M Sexton  8 ,  Denise Wootten  9
Affiliations
  • 1. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
  • 2. Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
  • 3. Novo Nordisk A/S, Novo Nordisk Park, Copenhagen, Denmark.
  • 4. Apigenex, Poděbradská 173/5, Prague 9 190 00, Czech Republic.
  • 5. Ramaciotti Centre for Cryo-Electron Microscopy, Monash University, Clayton, VIC 3168, Australia.
  • 6. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ 85259, USA.
  • 7. Graduate School of Medicine, University of Tokyo, N415, 7-3-1 Hongo, Bunkyo-ku, 113-0033 Tokyo, Japan. Electronic address: [email protected].
  • 8. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia. Electronic address: [email protected].
  • 9. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia. Electronic address: [email protected].
PMID: 33027691 DOI: 10.1016/j.molcel.2020.09.020
Abstract

Peptide drugs targeting class B1 G-protein-coupled receptors (GPCRs) can treat multiple diseases; however, there remains substantial interest in the development of orally delivered non-peptide drugs. Here, we reveal unexpected overlap between signaling and regulation of the glucagon-like peptide-1 (GLP-1) receptor by the non-peptide agonist PF 06882961 and GLP-1 that was not observed for another compound, CHU-128. Compounds from these patent series, including PF 06882961, are currently in clinical trials for treatment of type 2 diabetes. High-resolution cryoelectron microscopy (cryo-EM) structures reveal that the binding sites for PF 06882961 and GLP-1 substantially overlap, whereas CHU-128 adopts a unique binding mode with a more open receptor conformation at the extracellular face. Structural differences involving extensive water-mediated hydrogen bond networks could be correlated to functional data to understand how PF 06882961, but not CHU-128, can closely mimic the pharmacological properties of GLP-1. These findings will facilitate rational structure-based discovery of non-peptide agonists targeting class B GPCRs.

Keywords
G-protein-coupled receptor; GLP-1; cryoelectron microscopy; glucagon-like peptide-1 receptor; non-peptide agonists.
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