National Health and Medical Research Council (NHMRC, Australia)
1061044
オーストラリア
National Health and Medical Research Council (NHMRC, Australia)
1120919
オーストラリア
National Health and Medical Research Council (NHMRC, Australia)
1065410
オーストラリア
National Health and Medical Research Council (NHMRC, Australia)
1055134
オーストラリア
National Health and Medical Research Council (NHMRC, Australia)
1126857
オーストラリア
引用
ジャーナル: Mol Cell / 年: 2020 タイトル: Differential GLP-1R Binding and Activation by Peptide and Non-peptide Agonists. 著者: 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 ...著者: 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 / 要旨: 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.