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A more recent version of this article appeared on October 18, 2002
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C200465200v1
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Papers In Press, published online ahead of print August 29, 2002
J. Biol. Chem, 10.1074/jbc.C200465200
Submitted on August 16, 2002
Revised on August 29, 2002
Accepted on August 28, 2002

Crystal structure of the anticoagulant slow form of thrombin

Agustin O. Pineda, Savvas Savvides, Gabriel Waksman, and Enrico Di Cera

Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO 63110

Corresponding Author: enrico{at}biochem.wustl.edu

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 to 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 D189 in the S1 specificity pocket, a downward shift of the 190-193 strand, a rearrangement of the side chain of E192, and a significant shift in the position of the catalytic S195 that is no longer within H-bonding distance from H57. The structure of the slow form explains the reduced specificity toward synthetic and natural substrates and suggests a molecular basis for its anticoagulant properties.


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