Structure-activity relationships of recombinant hirudins.

The complex formation between thrombin and hirudin is unique among other serine proteinase-inhibitor complexes. The serpines occupy the specificity pocket of the active site of the target enzyme with an amino acid residue corresponding to the specificity of the enzyme at the P1 site of the substrate. In contrast, the Thr2 residue of hirudin approaches only the entrance of the pocket. The peptide chain of the inhibitors D-Phe-Pro-ArgCH2Cl and NAPAP is antiparallel to the enzyme backbone, whereas the N-terminal amino acids of hirudin run parallel. These unexpected interactions seem to contribute to a greater extent to the tight binding than the ionic interactions of the hirudin tail with the fibrinogen binding site of thrombin. Obviously, these interactions account for the unique selectivity of hirudin for thrombin.