InterPro: IPR000429 Proteinase inhibitor I14, hirudin

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.

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 (IPR001254) [1].

Hirudin is a potent thrombin inhibitor secreted by the salivary glands of the Hirudinaria manillensis (Buffalo leech) and Hirudo medicinalis (Medicinal leech) [2]. 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 [3], and the structure of a recombinant hirudin-thrombin complex has been determined by X-ray crystallography to 2.3A [4]. Hirudin consists of an N-terminal globular domain 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 1 making a hydrogen bond with the Ser195 O gamma atom of the catalytic site. The C-terminal domain makes numerous electrostatic interactions with an anion-binding exosite of thrombin, while the last five residues are in a helical loop that forms many hydrophobic contacts [4].