Ixolaris: a Factor Xa heparin-binding exosite inhibitor
| العنوان: | Ixolaris: a Factor Xa heparin-binding exosite inhibitor |
|---|---|
| المؤلفون: | Ivo M.B. Francischetti, Alireza R. Rezaie, Robson Q. Monteiro, José M. C. Ribeiro |
| المصدر: | Biochemical Journal. 387:871-877 |
| بيانات النشر: | Portland Press Ltd., 2005. |
| سنة النشر: | 2005 |
| مصطلحات موضوعية: | medicine.drug_mechanism_of_action, Factor Xa Inhibitor, Plasma protein binding, Biology, Biochemistry, chemistry.chemical_compound, Tissue factor pathway inhibitor, Thrombin, Prothrombinase, Zymogen, medicine, Amino Acid Sequence, Salivary Proteins and Peptides, Binding site, Molecular Biology, Binding Sites, Heparin, Factor X, Cell Biology, Molecular biology, chemistry, Factor Xa, Prothrombin, Factor Xa Inhibitors, Protein Binding, Research Article, medicine.drug |
| الوصف: | Ixolaris is a two-Kunitz TFPI (tissue factor pathway inhibitor) from the tick salivary gland. In contrast with human TFPI, Ixolaris binds tightly to the zymogen FX (Factor X) and to dansyl-Glu-Gly-Arg-chloromethyl ketone-treated FXa (DEGR-FXa; active-site-blocked FXa), indicating that exosites are involved in the FX(a)–Ixolaris interaction. Here we provide evidence that Ixolaris binds specifically to the FXa HBE (heparin-binding exosite), since (i) it markedly decreases the inhibition of FXa by the antithrombin–heparin but not the antithrombin–pentasaccharide complex, (ii) it impairs FXa binding to Sepharose-immobilized heparin, and (iii) it allosterically modulates the catalytic activity of FXa for small chromogenic substrates (S-2765). By using a series of recombinant FXa mutants in which the HBE is mutated, we have identified the importance of amino acids involved in the enzyme–inhibitor interaction as being in the following order: Arg-93≫Arg-165≥Lys-169>Lys-236>Lys-96>Arg-240>Arg-125. Ixolaris at appropriate concentrations also inhibits thrombin formation in vitro by the assembled prothrombinase complex, a process that is critically dependent on the FXa HBE. Ixolaris is the first inhibitor characterized to date that binds specifically to the FXa HBE. |
| تدمد: | 1470-8728 0264-6021 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e7b3a7ee17ee1136090bad1df3cb6db1Test https://doi.org/10.1042/bj20041738Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....e7b3a7ee17ee1136090bad1df3cb6db1 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14708728 02646021 |
|---|