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J. Biol. Chem., Vol. 275, Issue 51, 39827-39830, December 22, 2000
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From the Department of Biochemistry and Molecular Biophysics,
Washington University School of Medicine, St. Louis, Missouri
63110
Thrombin acts as a procoagulant when it cleaves
fibrinogen and promotes the formation of a fibrin clot and functions as
an anticoagulant when it activates protein C with the assistance of the
cofactor thrombomodulin. The dual function of thrombin in the blood
poses the challenge to turn the enzyme into a potent anticoagulant by
selectively abrogating fibrinogen cleavage. Using functional and
structural data, we have rationally designed a thrombin mutant,
W215A/E217A, that cleaves fibrinogen with a value of
kcat/Km about 20,000-fold
slower than wild-type but activates protein C in the presence of
thrombomodulin with a specificity comparable with wild-type. This
mutant demonstrates for the first time that the relative specificity of
thrombin toward fibrinogen and protein C can be completely reversed.
ACCELERATED PUBLICATION
Rational Design of a Potent Anticoagulant Thrombin*
*
This work was supported in part by National Institutes of
Health Research Grants HL49413 and HL58141.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Biochemistry
and Molecular Biophysics, Washington University School of Medicine, Box
8231, St. Louis, MO 63110. Tel.: 314-362-4185; Fax: 314-362-7183;
E-mail: enrico@caesar.wustl.edu.
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