Amerikanische Gesellschaft für Hirudotherapie

The molecular basis of thrombin allostery revealed by a 1.8 A structure of the "slow" form.

Research article published in Structure (London, England : 1993) (2003)

Zuletzt aktualisiert: June 18, 2026Geprüft von: ASH Editorial Board
Research article — evidence reviewArticle reference
Evidence: Research reportArzneimittelentwicklungSpeichel-PharmakologieHuntington et al. · Structure (London, England : 1993), 2003

Abstract

Thrombin participates in its own positive and negative feedback loops, and its allosteric state helps determine the hemostatic balance. Here we present the 1.8 A crystallographic structure of S195A thrombin in two conformational states: active site occupied and active site free. The active site-occupied form shows how thrombin can accommodate substrates, such as protein C. The active site-free form is in a previously unobserved closed conformation of thrombin, which satisfies all the conditions of the so-called "slow" form. A mechanism of allostery is revealed, which relies on the concerted movement of the disulphide bond between Cys168 and 182 and aromatic residues Phe227, Trp215, and Trp60d. These residues constitute an allosteric switch, which is flipped directly through sodium binding, resulting in the fast form with an open active site.

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'tResearch Support, U.S. Gov't, P.H.S.
Indexed MeSH termsAllosteric RegulationBinding SitesCrystallography, X-RayHumansModels, MolecularProtein ConformationSodiumThrombinTime Factors

Zusammenfassung

Thrombin participates in its own positive and negative feedback loops, and its allosteric state helps determine the hemostatic balance. Here we present the 1.8 A crystallographic structure of S195A thrombin in two conformational states: active site occupied and active site free.

Warum dies für die Hirudotherapie relevant ist

This study presented a 1.8 Å crystal structure of the S195A thrombin mutant in two conformational states—active site occupied and active site free—revealing a previously unobserved closed conformation satisfying conditions of the 'slow' form. The authors identified an allosteric switch involving the Cys168-Cys182 disulfide bond and aromatic residues Phe227, Trp215, and Trp60d that is flipped directly through sodium binding, resulting in the fast form with an open active site. The work advances understanding of thrombin allosteric regulation relevant to coagulation biology broadly. CAVEAT: No hirudin, leech-derived compounds, or hirudotherapy are mentioned anywhere in the abstract; the connection to ASH's domain is entirely indirect through thrombin structural biology, and no defensible leech link exists.

Zitation

The molecular basis of thrombin allostery revealed by a 1.8 A structure of the "slow" form.

Huntington et al. · Structure (London, England : 1993), 2003

DOI

Verwandter klinischer Kontext

Erfahren Sie, wie diese Forschung mit der klinischen Praxis verknüpft ist

Drug PipelineDrug DevelopmentDirect Thrombin InhibitorsSalivary Gland SecretionAnti-Inflammatory MechanismsSalivary ComplexHirudinAnticoagulation CompoundsHemostasisOtolaryngology

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