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

Research output: Contribution to journalJournal articleResearchpeer-review

  • Xin Zhang
  • Matthew J Belousoff
  • Peishen Zhao
  • Tin T Truong
  • Sheng Yu Ang
  • Christina Rye Underwood
  • Thomas Egebjerg
  • Petr Šenel
  • Gregory D Stewart
  • Yi-Lynn Liang
  • Alisa Glukhova
  • Hari Venugopal
  • Arthur Christopoulos
  • Sebastian G B Furness
  • Laurence J Miller
  • Steffen Reedtz-Runge
  • Christopher J Langmead
  • Radostin Danev
  • Patrick M Sexton
  • Denise Wootten

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.

Original languageEnglish
JournalMolecular Cell
Volume80
Issue number3
Pages (from-to)485-500
ISSN1097-2765
DOIs
Publication statusPublished - 2020

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