High-resolution crystal structure of human protease-activated receptor 1

Cheng Zhang, Yoga Srinivasan, Daniel H. Arlow, Juan Jose Fung, Daniel Palmer, Yaowu Zheng, Hillary F. Green, Anjali Pandey, Ron O. Dror, David E. Shaw, William I. Weis, Shaun R. Coughlin () and Brian K. Kobilka ()
Additional contact information
Cheng Zhang: Stanford University School of Medicine
Yoga Srinivasan: Cardiovascular Research Institute, University of California, San Francisco, 555 Mission Bay Boulevard South, S452P, San Francisco, California 94158, USA
Daniel H. Arlow: D. E. Shaw Research
Juan Jose Fung: Stanford University School of Medicine
Daniel Palmer: Cardiovascular Research Institute, University of California, San Francisco, 555 Mission Bay Boulevard South, S452P, San Francisco, California 94158, USA
Yaowu Zheng: Cardiovascular Research Institute, University of California, San Francisco, 555 Mission Bay Boulevard South, S452P, San Francisco, California 94158, USA
Hillary F. Green: D. E. Shaw Research
Anjali Pandey: Portola Pharmaceuticals, 270 East Grand Avenue
Ron O. Dror: D. E. Shaw Research
David E. Shaw: D. E. Shaw Research
William I. Weis: Stanford University School of Medicine
Shaun R. Coughlin: Cardiovascular Research Institute, University of California, San Francisco, 555 Mission Bay Boulevard South, S452P, San Francisco, California 94158, USA
Brian K. Kobilka: Stanford University School of Medicine

Nature, 2012, vol. 492, issue 7429, 387-392

Abstract: 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.

Date: 2012
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DOI: 10.1038/nature11701

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