3VW7

Crystal structure of human protease-activated receptor 1 (PAR1) bound with antagonist vorapaxar at 2.2 angstrom

3VW7 の概要

• エントリーDOI: 10.2210/pdb3vw7/pdb
• 分子名称: Proteinase-activated receptor 1, Lysozyme, ethyl [(1R,3aR,4aR,6R,8aR,9S,9aS)-9-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]ethenyl}-1-methyl-3-oxododecahydronaphtho[2,3-c]fur an-6-yl]carbamate, (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate, ... (6 entities in total)
• 機能のキーワード: high resolution structure, protease-activated receptor 1, inactive conformation, antagonist vorapaxar, g protein-coupled receptor, signaling protein, membrane protein, thrombin receptor-antagonist complex, signaling protein-antagonist complex, signaling protein/antagonist
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Cell membrane; Multi-pass membrane protein: P25116
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 58098.87

構造登録者

Zhang, C.,Srinivasan, Y.,Arlow, D.H.,Fung, J.J.,Palmer, D.,Zheng, Y.,Green, H.F.,Pandey, A.,Dror, R.O.,Shaw, D.E.,Weis, W.I.,Coughlin, S.R.,Kobilka, B.K. (登録日: 2012-08-07, 公開日: 2012-12-12, 最終更新日: 2024-11-20)

主引用文献

Zhang, C.,Srinivasan, Y.,Arlow, D.H.,Fung, J.J.,Palmer, D.,Zheng, Y.,Green, H.F.,Pandey, A.,Dror, R.O.,Shaw, D.E.,Weis, W.I.,Coughlin, S.R.,Kobilka, B.K.
High-resolution crystal structure of human protease-activated receptor 1
Nature, 492:387-392, 2012

PubMed Abstract: Protease-activated receptor 1 (PAR1) is the prototypical member of a family of G-protein-coupled receptors that mediate cellular responses to thrombin and related proteases. Thrombin irreversibly activates PAR1 by cleaving the amino-terminal exodomain of the receptor, which exposes a tethered peptide ligand that binds the heptahelical bundle of the receptor to affect G-protein activation. Here we report the 2.2 Å resolution crystal structure of human PAR1 bound to vorapaxar, a PAR1 antagonist. The structure reveals an unusual mode of drug binding that explains how a small molecule binds virtually irreversibly to inhibit receptor activation by the tethered ligand of PAR1. In contrast to deep, solvent-exposed binding pockets observed in other peptide-activated G-protein-coupled receptors, the vorapaxar-binding pocket is superficial but has little surface exposed to the aqueous solvent. Protease-activated receptors are important targets for drug development. The structure reported here will aid the development of improved PAR1 antagonists and the discovery of antagonists to other members of this receptor family.

PubMed: 23222541
DOI: 10.1038/nature11701

実験手法

X-RAY DIFFRACTION (2.2 Å)