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Title | Differential GLP-1R Binding and Activation by Peptide and Non-peptide Agonists. |
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Journal, issue, pages | Mol Cell, Vol. 80, Issue 3, Page 485-500.e7, Year 2020 |
Publish date | Nov 5, 2020 |
Authors | Xin Zhang / Matthew J Belousoff / Peishen Zhao / Albert J Kooistra / 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 / David E Gloriam / Radostin Danev / Patrick M Sexton / Denise Wootten / |
PubMed 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. ...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. |
External links | Mol Cell / PubMed:33027691 |
Methods | EM (single particle) |
Resolution | 2.1 - 2.5 Å |
Structure data | EMDB-21992, PDB-6x18: EMDB-21993, PDB-6x19: EMDB-21994, PDB-6x1a: |
Chemicals | ChemComp-HOH: ChemComp-UK1: ChemComp-UK4: |
Source |
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Keywords | MEMBRANE PROTEIN / G-coupled protein receptor / GPCR / non-peptide agonist |