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.
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Research Article|
April 26 2005
Ixolaris: a Factor Xa heparin-binding exosite inhibitor Available to Purchase
Robson Q. MONTEIRO;
Robson Q. MONTEIRO
*Instituto de Bioquímica Médica, Programa de Biologia Estrutural, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-590, Brazil
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Alireza R. REZAIE;
Alireza R. REZAIE
†Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, MO 63104, U.S.A.
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José M. C. RIBEIRO;
José M. C. RIBEIRO
‡Section of Medical Entomology, Laboratory of Malaria and Vector Research, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20892–8132, U.S.A.
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Ivo M. B. FRANCISCHETTI
Ivo M. B. FRANCISCHETTI
1
‡Section of Medical Entomology, Laboratory of Malaria and Vector Research, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20892–8132, U.S.A.
1To whom correspondence should be addressed: LMVR, NIAID, NIH, 12735 Twinbrook Parkway, Twinbrook III Bldg, Room 2E-28, Rockville, MD 20892–8132, U.S.A. (email [email protected]).
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Publisher: Portland Press Ltd
Received:
October 13 2004
Revision Received:
December 01 2004
Accepted:
December 23 2004
Accepted Manuscript online:
December 23 2004
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2005
Biochem J (2005) 387 (3): 871–877.
Article history
Received:
October 13 2004
Revision Received:
December 01 2004
Accepted:
December 23 2004
Accepted Manuscript online:
December 23 2004
Citation
Robson Q. MONTEIRO, Alireza R. REZAIE, José M. C. RIBEIRO, Ivo M. B. FRANCISCHETTI; Ixolaris: a Factor Xa heparin-binding exosite inhibitor. Biochem J 1 May 2005; 387 (3): 871–877. doi: https://doi.org/10.1042/BJ20041738
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