title: High-resolution crystal structure of human protease-activated receptor 1.
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.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Yoga
authors.initials: Y
authors.lastname: Srinivasan
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Arlow
authors.forename: Juan Jose
authors.initials: JJ
authors.lastname: Fung
authors.forename: Daniel
authors.initials: D
authors.lastname: Palmer
authors.forename: Yaowu
authors.initials: Y
authors.lastname: Zheng
authors.forename: Hillary F
authors.initials: HF
authors.lastname: Green
authors.forename: Anjali
authors.initials: A
authors.lastname: Pandey
authors.forename: Ron O
authors.initials: RO
authors.lastname: Dror
authors.forename: David E
authors.initials: DE
authors.lastname: Shaw
authors.forename: William I
authors.initials: WI
authors.lastname: Weis
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Coughlin
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kobilka
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D003460:Crystallization; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000235:genetics; D006801:Humans; D006868:Hydrolysis; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009203:Myocardial Infarction / Q000517:prevention & control; D011487:Protein Conformation; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D044463:Receptor, PAR-1 / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000145:classification; D018179:Receptors, Thrombin; D010975:Platelet Aggregation Inhibitors
chemical_list: D007783:Lactones; D008024:Ligands; D011725:Pyridines; D044463:Receptor, PAR-1; D043562:Receptors, G-Protein-Coupled; D018179:Receptors, Thrombin; C530299:vorapaxar; D010975:Platelet Aggregation Inhibitors