Crystal Structure of Thrombin in Complex with S-Variegin: Insights of a Novel Mechanism of Inhibition and Design of Tunable Thrombin Inhibitors | Zendy

Cho Yeow Koh | Zendy; Sundramurthy Kumar | Zendy; Mária Kazimírová | Zendy; Adriana Patrícia | Zendy; Uvaraj P. Radhakrishnan | Zendy; Seongcheol Kim | Zendy; Pudur Jagadeeswaran | Zendy; Takayuki Imamura | Zendy; J. Mizuguchi | Zendy; Sadaaki Iwanaga | Zendy; Kunchithapadam Swaminathan | Zendy; R. Manjunatha Kini | Zendy

Open Access

Crystal Structure of Thrombin in Complex with S-Variegin: Insights of a Novel Mechanism of Inhibition and Design of Tunable Thrombin Inhibitors

Author(s) -

Cho Yeow Koh,

Sundramurthy Kumar,

Mária Kazimírová,

Adriana Patrícia,

Uvaraj P. Radhakrishnan,

Seongcheol Kim,

Pudur Jagadeeswaran,

Takayuki Imamura,

J. Mizuguchi,

Sadaaki Iwanaga,

Kunchithapadam Swaminathan,

R. Manjunatha Kini

Publication year - 2011

Publication title -

plos one

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 0.99

H-Index - 332

ISSN - 1932-6203

DOI - 10.1371/journal.pone.0026367

Subject(s) - thrombin , discovery and development of direct thrombin inhibitors , hirudin , chemistry , bivalirudin , active site , antithrombotic , cleavage (geology) , antithrombins , biophysics , small molecule , non competitive inhibition , in vivo , biochemistry , stereochemistry , pharmacology , biology , enzyme , medicine , platelet , immunology , paleontology , cardiology , microbiology and biotechnology , psychiatry , percutaneous coronary intervention , myocardial infarction , fracture (geology)

The inhibition of thrombin is one of the important treatments of pathological blood clot formation. Variegin, isolated from the tropical bont tick, is a novel molecule exhibiting a unique ‘two-modes’ inhibitory property on thrombin active site (competitive before cleavage, noncompetitive after cleavage). For the better understanding of its function, we have determined the crystal structure of the human α-thrombin:synthetic-variegin complex at 2.4 Å resolution. The structure reveals a new mechanism of thrombin inhibition by disrupting the charge relay system. Based on the structure, we have designed 17 variegin variants, differing in potency, kinetics and mechanism of inhibition. The most active variant is about 70 times more potent than the FDA-approved peptidic thrombin inhibitor, hirulog-1/bivalirudin. In vivo antithrombotic effects of the variegin variants correlate well with their in vitro affinities for thrombin. Our results encourage that variegin and the variants show strong potential for the development of tunable anticoagulants.

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