3VW7

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

Summary for 3VW7

• Entry DOI: 10.2210/pdb3vw7/pdb
• Descriptor: 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)
• Functional Keywords: 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
• Biological source: Homo sapiens (human); More
• Cellular location: Cell membrane; Multi-pass membrane protein: P25116
• Total number of polymer chains: 1
• Total formula weight: 58098.87

Authors

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. (deposition date: 2012-08-07, release date: 2012-12-12, Last modification date: 2024-11-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.2 Å)