6X19

Non peptide agonist CHU-128, bound to Glucagon-Like peptide-1 (GLP-1) Receptor

6X19 の概要

• エントリーDOI: 10.2210/pdb6x19/pdb
• 関連するPDBエントリー: 6X18
• EMDBエントリー: 21992 21993 21994
• 分子名称: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (7 entities in total)
• 機能のキーワード: g-coupled protein receptor, gpcr, membrane protein, non-peptide agonist
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 160992.44

構造登録者

Belousoff, M.J.,Zhang, X.,Danev, R. (登録日: 2020-05-18, 公開日: 2020-09-09, 最終更新日: 2025-06-04)

主引用文献

Zhang, X.,Belousoff, M.J.,Zhao, P.,Kooistra, A.J.,Truong, T.T.,Ang, S.Y.,Underwood, C.R.,Egebjerg, T.,Senel, P.,Stewart, G.D.,Liang, Y.L.,Glukhova, A.,Venugopal, H.,Christopoulos, A.,Furness, S.G.B.,Miller, L.J.,Reedtz-Runge, S.,Langmead, C.J.,Gloriam, D.E.,Danev, R.,Sexton, P.M.,Wootten, D.
Differential GLP-1R Binding and Activation by Peptide and Non-peptide Agonists.
Mol.Cell, 80:485-, 2020

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. 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.

PubMed: 33027691
DOI: 10.1016/j.molcel.2020.09.020

実験手法

ELECTRON MICROSCOPY (2.1 Å)