High-resolution crystal structure of human protease-activated receptor 1
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Open Access
- 9 December 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 492 (7429), 387-392
- https://doi.org/10.1038/nature11701
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.Keywords
This publication has 74 references indexed in Scilit:
- Structure of the δ-opioid receptor bound to naltrindoleNature, 2012
- How Robust Are Protein Folding Simulations with Respect to Force Field Parameterization?Biophysical Journal, 2011
- Structure and function of an irreversible agonist-β2 adrenoceptor complexNature, 2011
- Structure of a nanobody-stabilized active state of the β2 adrenoceptorNature, 2011
- Update of the CHARMM All-Atom Additive Force Field for Lipids: Validation on Six Lipid TypesThe Journal of Physical Chemistry B, 2010
- CHARMM general force field: A force field for drug‐like molecules compatible with the CHARMM all‐atom additive biological force fieldsJournal of Computational Chemistry, 2009
- Extending the treatment of backbone energetics in protein force fields: Limitations of gas‐phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulationsJournal of Computational Chemistry, 2004
- All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of ProteinsThe Journal of Physical Chemistry B, 1998
- [20] Processing of X-ray diffraction data collected in oscillation modeMethods in Enzymology, 1997
- VMD: Visual molecular dynamicsJournal of Molecular Graphics, 1996