Crystal structure of thrombin in complex with S-Variegin: Insights of a novel mechanism of inhibition and design of tunable thrombin inhibitors
Koh, Cho Yeow; Kumar, Sundramurthy; Kazimirova, Maria; Nuttall, Patricia A.; Radhakrishnan, Uvaraj P.; Kim, Seongcheol; Jagadeeswaran, Pudur; Imamura, Takayuki; Mizuguchi, Jun; Iwanaga, Sadaaki; Swaminathan, Kunchithapadam; Kini, R. Manjunatha. 2011 Crystal structure of thrombin in complex with S-Variegin: Insights of a novel mechanism of inhibition and design of tunable thrombin inhibitors. PLoS ONE, 6 (10), e26367. 16, pp. 10.1371/journal.pone.0026367Full text not available from this repository.
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.
|Programmes:||CEH Topics & Objectives 2009 onwards > Biodiversity|
|Additional Information:||PLoS ONE is an open access journal. Click on the OFFICIAL URL link to access full text.|
|NORA Subject Terms:||Biology and Microbiology|
|Date made live:||25 Jun 2012 13:11|
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