High-resolution Crystal Structure of Human Protease-activated Receptor 1

Overview

Journal Nature

Specialty Science

Date 2012 Dec 11

PMID 23222541

Citations 205

Authors

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

Brian K Kobilka

Affiliations

Soon will be listed here.

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.

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