Differential GLP-1R Binding and Activation by Peptide and Non-peptide Agonists
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- Differential GLP-1R Binding and Activation by Peptide and Non-peptide Agonists
Accepted author manuscript, 4.56 MB, PDF document
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 language | English |
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Journal | Molecular Cell |
Volume | 80 |
Issue number | 3 |
Pages (from-to) | 485-500 |
ISSN | 1097-2765 |
DOIs | |
Publication status | Published - 2020 |
Bibliographical note
Copyright © 2020 Elsevier Inc. All rights reserved.
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