Journal Article

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

Dror, Ron O., Zhang, Cheng, Pandey, Anjali, Srinivasan, Yoga, Fung, Juan Jose, Green, Hillary F., Kobilka, Brian K., Shaw, David E., Coughlin, Shaun R., Zheng, Yaowu, Arlow, Daniel H., Palmer, Daniel, Weis, William I.

2012

Overview

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. The X-ray crystal structure of the human G-protein-coupled receptor protease-activated receptor 1 (PAR1) bound to the antagonist vorapaxar is solved, revealing an unusual method of drug binding that should facilitate the development of improved PAR1-selective antagonists. Thrombin receptor structure The X-ray crystal structure of the human protease-activated receptor 1 (PAR1) bound to vorapaxar, a PAR1 antagonist, has been determined at 2.2 Å resolution. PAR1, also known as the thrombin receptor, is a G protein-coupled receptor that mediates cellular responses to the coagulation protease thrombin and related proteases. Vorapaxar was recently shown to prevent myocardial infarction in at-risk patients, and knowledge of the PAR structure will be relevant to the design of PAR1 antagonists with better drug properties.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/154/309/2420 / 631/250/2500 / 631/378/194 / 631/45/535 / 631/535/1266 / 631/92/436 / Amino Acid Motifs / Amino acids / Analytical, structural and metabolic biochemistry / Animal experimentation / Binding Sites / Biological and medical sciences / Cell interaction / Cell receptors / Cell structures and functions / Crystalline structure / Crystallization / Crystallography, X-Ray / Crystals / Enzyme Activation - genetics / Fundamental and applied biological sciences. Psychology / Heart attacks / Humanities and Social Sciences / Humans / Hydrolysis / Lactones - chemistry / Lactones - pharmacology / Ligands / Methods / Miscellaneous / Models, Molecular / Molecular and cellular biology / Molecular biophysics / Molecular Dynamics Simulation / multidisciplinary / Myocardial Infarction - prevention & control / Peptides / Physiological aspects / Proteases / Protein Conformation / Proteins / Pyridines - chemistry / Pyridines - pharmacology / Receptor, PAR-1 - agonists / Receptor, PAR-1 - antagonists & inhibitors / Receptor, PAR-1 - chemistry / Receptor, PAR-1 - metabolism / Receptors, G-Protein-Coupled - chemistry / Receptors, G-Protein-Coupled - classification / Receptors, Thrombin / Science / Solvents / Structure / Structure in molecular biology