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

Research article published in The EMBO journal (1996)

Última actualización: 18 de junio de 2026Revisado por: ASH Editorial Board

Artículo de investigación — revisión de evidenciaReferencia del artículo

Evidence: Preclinical (animal)Desarrollo de fármacosvan 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

Resumen

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

Por qué esto importa para la hirudoterapia

Este artículo describe la estructura cristalina de la ornitodorina, un potente inhibidor de la trombina (Ki ~10^-12 M) aislado de la garrapata blanda Ornithodoros moubata, en complejo con trombina. El resumen muestra que la ornitodorina es un inhibidor tipo Kunitz de dos dominios, cuyo extremo N-terminal ocupa el sitio activo de la trombina de manera reminiscente de la interacción trombina-hirudina, mientras que su dominio C-terminal se une al exosito de reconocimiento del fibrinógeno. Para la ASH, esto es relevante porque aporta un marco estructural comparativo para comprender los mecanismos convergentes de inhibición potente de la trombina entre especies hematófagas, destacando cómo la estrategia de unión de doble sitio de la hirudina se ve reflejada en una molécula derivada de garrapata. La advertencia es que este estudio no involucra sanguijuelas ni moléculas derivadas de sanguijuela alguna; constituye únicamente una referencia estructural comparativa e indirecta.