Title

Structural Basis for Thrombin Activation of a Protease-Activated Receptor

Document Type

Article

Publication Date

11-1-2003

Publication Title

Cell Chemical Biology

Abstract

Protease-activated G protein-coupled receptors (PAR1–4) are tethered-ligand receptors that are activated by proteolytic cleavage of the extracellular domain (exodomain) of the receptor. PAR1, the prototypic member of the PAR family, is the high-affinity thrombin receptor of platelets and vascular endothelium and plays a critical role in blood coagulation, thrombosis, and inflammation. Here, we describe the solution structure of the thrombin-cleaved exodomain of PAR1. The side chains of a hydrophobic hirudin-like (Hir) sequence and adjacent anionic motif project into solution. Docking of the exodomain Hir sequence to exosite I of thrombin reveals that the tethered ligand in the cleaved exodomain bends away from thrombin, leaving its active site available to another large macromolecular substrate. The N-terminal ligand is longer than anticipated and forms an intramolecular complex with a region located in the C terminus of the exodomain. Mutational analysis confirmed that this C-terminal region is a ligand binding site for both intra- and intermolecular ligands. A lipidated-ligand binding site peptide was found to be an effective inhibitor of thrombin-induced platelet aggregation.

Volume

10

Issue

11

First Page

1033

Last Page

1041

DOI

https://doi.org/10.1016/j.chembiol.2003.10.014

ISSN

2451-9456

Comments

ESSN: 2451-9456

Rights

© 2003 Cell Press

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