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Science 6 September 1996:
Vol. 273. no. 5280, pp. 1389 - 1391
DOI: 10.1126/science.273.5280.1389
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Reports
Enhanced Protein C Activation and Inhibition of Fibrinogen
Cleavage by a Thrombin Modulator
David T. Berg,
Michael R. Wiley,
Brian W. Grinnell
*
A modulator of the enzymatic activity of human thrombin, designated
LY254603, was identified that enhances the thrombin-catalyzed
generation of the anticoagulant factor activated protein C, yet
inhibits thrombin-dependent fibrinogen clotting. By means of mutant
substrates, it was shown that LY254603 mediates the change in enzymatic
substrate specificity through an alteration in thrombin's S3 substrate
recognition site, a mechanism that appeared to be independent of
allosteric changes induced by either sodium ions or by thrombomodulin.
This compound may represent the prototype of a class of agents that
specifically modulates the balance between thrombin's procoagulant and
anticoagulant functions.
Cardiovascular Research Division, Lilly Research Laboratories,
Indianapolis, IN 46285-0444, USA.
*
To whom correspondence should be addressed. E-mail:
grinnell_brian{at}lilly.com
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
- Molecular Dissection of Na+ Binding to Thrombin.
- A. O. Pineda, C. J. Carrell, L. A. Bush, S. Prasad, S. Caccia, Z.-W. Chen, F. S. Mathews, and E. Di Cera (2004)
J. Biol. Chem.
279, 31842-31853
| Abstract »
| Full Text »
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- New Anticoagulant Drugs.
- J. I. Weitz and J. Hirsh (2001)
Chest
119, 95S-107S
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- Advances in Therapy and the Management of Antithrombotic Drugs for Venous Thromboembolism.
- J. E. Ansell, J. I. Weitz, and A. J. Comerota (2000)
Hematology
2000, 266-284
| Abstract »
| Full Text »
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- Selective Loss of Fibrinogen Clotting in a Loop-less Thrombin.
- Q. D. Dang, M. Sabetta, and E. Di Cera (1997)
J. Biol. Chem.
272, 19649-19651
| Abstract »
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