The ornithodorin-thrombin crystal structure, a key to the TAP enigma?

Research article published in The EMBO journal (1996)

Zuletzt aktualisiert: June 18, 2026Geprüft von: ASH Editorial Board

Research article — evidence reviewArticle reference

Evidence: Preclinical (animal)Arzneimittelentwicklungvan de Locht A et al. · The EMBO journal, 1996

Abstract

Ornithodorin, isolated from the blood sucking soft tick Ornithodoros moubata, is a potent (Ki = 10(-12) M) and highly selective thrombin inhibitor. Internal sequence homology indicates a two domain protein. Each domain resembles the Kunitz inhibitor basic pancreatic trypsin inhibitor (BPTI) and also the tick anticoagulant peptide (TAP) isolated from the same organism. The 3.1 A crystal structure of the ornithodorin-thrombin complex confirms that both domains of ornithodorin exhibit a distorted BPTI-like fold. The N-terminal portion and the C-terminal helix of each domain are structurally very similar to BPTI, whereas the regions corresponding to the binding loop of BPTI adopt different conformations. Neither of the two 'reactive site loops' of ornithodorin contacts the protease in the ornithodorin-thrombin complex. Instead, the N-terminal residues of ornithodorin bind to the active site of thrombin, reminiscent of the thrombin-hirudin interaction. The C-terminal domain binds at the fibrinogen recognition exosite. Molecular recognition of its target protease by this double-headed Kunitz-type inhibitor diverges considerably from other members of this intensely studied superfamily. The complex structure provides a model to explain the perplexing results of mutagenesis studies on the TAP-factor Xa interaction.

Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.

Publication typeJournal ArticleResearch Support, Non-U.S. Gov't

Indexed MeSH termsAmino Acid SequenceAnimalsAprotininArthropod ProteinsBinding SitesCrystallography, X-RayEnzyme InhibitorsFactor XaIntercellular Signaling Peptides and ProteinsModels, MolecularMolecular Sequence DataPeptides

Zusammenfassung

Ornithodorin, isolated from the blood sucking soft tick Ornithodoros moubata, is a potent (Ki = 10(-12) M) and highly selective thrombin inhibitor.

Warum dies für die Hirudotherapie relevant ist

This article describes the crystal structure of ornithodorin, a potent thrombin inhibitor (Ki ~10^-12 M) isolated from the soft tick Ornithodoros moubata, in complex with thrombin. The abstract shows ornithodorin is a two-domain Kunitz-type inhibitor whose N-terminus occupies the thrombin active site in a manner reminiscent of the thrombin-hirudin interaction, while its C-terminal domain binds the fibrinogen recognition exosite. For ASH, this is relevant because it provides a comparative structural framework for understanding convergent mechanisms of potent thrombin inhibition across blood-feeding species, highlighting how hirudin's dual-site binding strategy is mirrored in a tick-derived molecule. The caveat is that this study involves no leeches or leech-derived molecules whatsoever; it is an indirect, comparative structural reference only.