FIGURE 2. Mechanism of PAR1 activation.

Thrombin (large green sphere) recognizes the N-terminal exodomain of the G-protein-coupled thrombin receptor PAR1. This interaction uses sites both N-terminal (small blue sphere) and C-terminal (small pink oval) to the thrombin cleavage site. The latter sequence resembles the C-terminal tail of the thrombin inhibitor hirudin and binds to thrombin in an analogous manner. Thrombin cleaves the peptide bond between receptor residues Arg 41 and Ser 42. This serves to unmask a new N terminus, beginning with the sequence SFLLRN (diamond) that functions as a tethered ligand, docking intramolecularly with the body of the receptor to effect transmembrane signalling. Synthetic SFLLRN peptide, which mimics the tethered ligand sequence, will function as an agonist independently of receptor cleavage. Thus PAR1 is, in essence, a peptide receptor that carries its own ligand, the latter being active only after receptor cleavage.