Revisiting antithrombotic therapeutics; sculptin, a novel specific, competitive, reversible, scissile and tight binding inhibitor of thrombin
Abstract Thrombin is a multifunctional enzyme with a key role in the coagulation cascade. Its functional modulation can culminate into normal blood coagulation or thrombosis. Thus, the identification of novel potent inhibitors of thrombin are of immense importance. Sculptin is the first specific thr...
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| Format: | Article |
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Nature Portfolio
2017-05-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-01486-w |
| _version_ | 1818683855596421120 |
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| author | Asif Iqbal Mauricio Barbugiani Goldfeder Rafael Marques-Porto Huma Asif Jean Gabriel de Souza Fernanda Faria Ana Marisa Chudzinski-Tavassi |
| author_facet | Asif Iqbal Mauricio Barbugiani Goldfeder Rafael Marques-Porto Huma Asif Jean Gabriel de Souza Fernanda Faria Ana Marisa Chudzinski-Tavassi |
| author_sort | Asif Iqbal |
| collection | DOAJ |
| description | Abstract Thrombin is a multifunctional enzyme with a key role in the coagulation cascade. Its functional modulation can culminate into normal blood coagulation or thrombosis. Thus, the identification of novel potent inhibitors of thrombin are of immense importance. Sculptin is the first specific thrombin inhibitor identified in the transcriptomics analysis of tick’s salivary glands. It consists of 168 residues having four similar repeats and evolutionary diverged from hirudin. Sculptin is a competitive, specific and reversible inhibitor of thrombin with a Ki of 18.3 ± 1.9 pM (k on 4.04 ± 0.03 × 107 M−1 s−1 and k off 0.65 ± 0.04 × 10−3 s−1). It is slowly consumed by thrombin eventually losing its activity. Contrary, sculptin is hydrolyzed by factor Xa and each polypeptide fragment is able to inhibit thrombin independently. A single domain of sculptin alone retains ~45% of inhibitory activity, which could bind thrombin in a bivalent fashion. The formation of a small turn/helical-like structure by active site binding residues of sculptin might have made it a more potent thrombin inhibitor. In addition, sculptin prolongs global coagulation parameters. In conclusion, sculptin and its independent domain(s) have strong potential to become novel antithrombotic therapeutics. |
| first_indexed | 2024-12-17T10:41:22Z |
| format | Article |
| id | doaj.art-ba1295f0327f41e988619873c275f432 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-17T10:41:22Z |
| publishDate | 2017-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-ba1295f0327f41e988619873c275f4322022-12-21T21:52:15ZengNature PortfolioScientific Reports2045-23222017-05-017111410.1038/s41598-017-01486-wRevisiting antithrombotic therapeutics; sculptin, a novel specific, competitive, reversible, scissile and tight binding inhibitor of thrombinAsif Iqbal0Mauricio Barbugiani Goldfeder1Rafael Marques-Porto2Huma Asif3Jean Gabriel de Souza4Fernanda Faria5Ana Marisa Chudzinski-Tavassi6Laboratory of Biochemistry and Biophysics, Butantan InstituteLaboratory of Biochemistry and Biophysics, Butantan InstituteLaboratory of Biochemistry and Biophysics, Butantan InstituteLaboratory of Gene Expression in Eukaryotes, Butantan InstituteLaboratory of Biochemistry and Biophysics, Butantan InstituteLaboratory of Biochemistry and Biophysics, Butantan InstituteLaboratory of Biochemistry and Biophysics, Butantan InstituteAbstract Thrombin is a multifunctional enzyme with a key role in the coagulation cascade. Its functional modulation can culminate into normal blood coagulation or thrombosis. Thus, the identification of novel potent inhibitors of thrombin are of immense importance. Sculptin is the first specific thrombin inhibitor identified in the transcriptomics analysis of tick’s salivary glands. It consists of 168 residues having four similar repeats and evolutionary diverged from hirudin. Sculptin is a competitive, specific and reversible inhibitor of thrombin with a Ki of 18.3 ± 1.9 pM (k on 4.04 ± 0.03 × 107 M−1 s−1 and k off 0.65 ± 0.04 × 10−3 s−1). It is slowly consumed by thrombin eventually losing its activity. Contrary, sculptin is hydrolyzed by factor Xa and each polypeptide fragment is able to inhibit thrombin independently. A single domain of sculptin alone retains ~45% of inhibitory activity, which could bind thrombin in a bivalent fashion. The formation of a small turn/helical-like structure by active site binding residues of sculptin might have made it a more potent thrombin inhibitor. In addition, sculptin prolongs global coagulation parameters. In conclusion, sculptin and its independent domain(s) have strong potential to become novel antithrombotic therapeutics.https://doi.org/10.1038/s41598-017-01486-w |
| spellingShingle | Asif Iqbal Mauricio Barbugiani Goldfeder Rafael Marques-Porto Huma Asif Jean Gabriel de Souza Fernanda Faria Ana Marisa Chudzinski-Tavassi Revisiting antithrombotic therapeutics; sculptin, a novel specific, competitive, reversible, scissile and tight binding inhibitor of thrombin Scientific Reports |
| title | Revisiting antithrombotic therapeutics; sculptin, a novel specific, competitive, reversible, scissile and tight binding inhibitor of thrombin |
| title_full | Revisiting antithrombotic therapeutics; sculptin, a novel specific, competitive, reversible, scissile and tight binding inhibitor of thrombin |
| title_fullStr | Revisiting antithrombotic therapeutics; sculptin, a novel specific, competitive, reversible, scissile and tight binding inhibitor of thrombin |
| title_full_unstemmed | Revisiting antithrombotic therapeutics; sculptin, a novel specific, competitive, reversible, scissile and tight binding inhibitor of thrombin |
| title_short | Revisiting antithrombotic therapeutics; sculptin, a novel specific, competitive, reversible, scissile and tight binding inhibitor of thrombin |
| title_sort | revisiting antithrombotic therapeutics sculptin a novel specific competitive reversible scissile and tight binding inhibitor of thrombin |
| url | https://doi.org/10.1038/s41598-017-01486-w |
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