| Title |
Crystal Structure of Thrombin in Complex with S-Variegin: Insights of a Novel Mechanism of Inhibition and Design of Tunable Thrombin Inhibitors
|
|---|---|
| Published in |
PLOS ONE, October 2011
|
| DOI | 10.1371/journal.pone.0026367 |
| Pubmed ID | |
| Authors |
Cho Yeow Koh, Sundramurthy Kumar, Maria Kazimirova, Patricia A. Nuttall, Uvaraj P. Radhakrishnan, Seongcheol Kim, Pudur Jagadeeswaran, Takayuki Imamura, Jun Mizuguchi, Sadaaki Iwanaga, Kunchithapadam Swaminathan, R. Manjunatha Kini |
| Abstract |
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. |
Mendeley readers
The data shown below were compiled from readership statistics for 48 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| India | 1 | 2% |
| Australia | 1 | 2% |
| Unknown | 46 | 96% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Bachelor | 9 | 19% |
| Researcher | 6 | 13% |
| Student > Master | 6 | 13% |
| Student > Ph. D. Student | 4 | 8% |
| Student > Doctoral Student | 3 | 6% |
| Other | 8 | 17% |
| Unknown | 12 | 25% |
| Readers by discipline | Count | As % |
|---|---|---|
| Agricultural and Biological Sciences | 15 | 31% |
| Biochemistry, Genetics and Molecular Biology | 11 | 23% |
| Medicine and Dentistry | 2 | 4% |
| Pharmacology, Toxicology and Pharmaceutical Science | 1 | 2% |
| Immunology and Microbiology | 1 | 2% |
| Other | 5 | 10% |
| Unknown | 13 | 27% |