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Originally published In Press as doi:10.1074/jbc.C200465200 on August 29, 2002

J. Biol. Chem., Vol. 277, Issue 43, 40177-40180, October 25, 2002
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ACCELERATED PUBLICATION
Crystal Structure of the Anticoagulant Slow Form of Thrombin*

Agustin O. PinedaDagger , Savvas N. Savvides§, Gabriel Waksman, and Enrico Di Cera

From the Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110

Using the thrombin mutant R77aA devoid of the site of autoproteolytic degradation at exosite I, we have solved for the first time the structure of thrombin free of any inhibitors and effector molecules and stabilized in the Na+-free slow form. The slow form shows subtle differences compared with the currently available structures of the Na+-bound fast form that carry inhibitors at the active site or exosite I. The most notable differences are the displacement of Asp-189 in the S1 specificity pocket, a downward shift of the 190-193 strand, a rearrangement of the side chain of Glu-192, and a significant shift in the position of the catalytic Ser-195 that is no longer within H-bonding distance from His-57. The structure of the slow form explains the reduced specificity toward synthetic and natural substrates and suggests a molecular basis for its anticoagulant properties.

* This work was supported in part by National Institutes of Health Research Grants HL49413 and HL58141 (to E. D. C.).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.

The atomic coordinates and the structure factors (code 1MH0) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

Dagger Recipient of a Fellowship from the American Heart Association.

§ Present address: Dienst Ultrastructuur, Vrije Universiteit Brussel, Paardenstraat 65, B-1640 Sint Genesius Rode, Belgium.

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: 314-747-5354; E-mail: enrico@biochem.wustl.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.


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