<p>Peptide proteinase inhibitors can be found as single domain proteins or as single or multiple domains within proteins; these are referred to as either simple or compound inhibitors, respectively. In many cases they are synthesised as part of a larger precursor protein, either as a prepropeptide or as an N-terminal domain associated with an inactive peptidase or zymogen. This domain prevents access of the substrate to the active site. Removal of the N-terminal inhibitor domain either by interaction with a second peptidase or by autocatalytic cleavage activates the zymogen. Other inhibitors interact direct with proteinases using a simple noncovalent lock and key mechanism; while yet others use a conformational change-based trapping mechanism that depends on their structural and thermodynamic properties. </p><p>The group of proteins belongs to the hirudin family; they are proteinase inhibitors belongs to MEROPS inhibitor family I14, clan IM; they inhibit serine peptidases of the S1 family (<db_xref db="INTERPRO" dbkey="IPR001254"/>) [<cite idref="PUB00014133"/>].</p> <p>Hirudin is a potent thrombin inhibitor secreted by the salivary glands ofthe <taxon tax_id="6419">Hirudinaria manillensis</taxon> (Buffalo leech) and <taxon tax_id="6421">Hirudo medicinalis</taxon> (Medicinal leech) [<cite idref="PUB00004614"/>]. It forms a stable non-covalent complex with alpha-thrombin, thereby abolishing its ability to cleave fibrinogen. The structure of hirudin has been solved by NMR [<cite idref="PUB00000305"/>], and the structure of a recombinant hirudin-thrombin complex has been determined by X-raycrystallography to 2.3A [<cite idref="PUB00005129"/>]. Hirudin consists of an N-terminal globulardomain and an extended C-terminal domain. Residues 1-3 form a parallel beta-strand with residues 214-217 of thrombin, the nitrogen atom of residue 1making a hydrogen bond with the Ser195 O gamma atom of the catalytic site.The C-terminal domain makes numerous electrostatic interactions with ananion-binding exosite of thrombin, while the last five residues are ina helical loop that forms many hydrophobic contacts [<cite idref="PUB00005129"/>].</p>