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J. Biol. Chem., Vol. 279, Issue 32, 33882-33889, August 6, 2004

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Substrate-induced Conformational Changes in Human UMP/CMP Kinase^*

Dario Segura-Peña, Nikolina Sekulic, Stephan Ort, Manfred Konrad, and Arnon Lavie¶

From the University of Illinois at Chicago, Department of Biochemistry and Molecular Genetics, Chicago, Illinois 60607 and the Max Planck Institute for Biophysical Chemistry, Department of Molecular Genetics, Am Fassberg 11, 37077 Göttingen, Germany

Human UMP/CMP kinase plays a crucial role in supplying precursors for nucleic acid synthesis by catalyzing the conversion of UMP, CMP, and dCMP into their diphosphate form. In addition, this kinase is an essential component of the activation cascade of medicinally relevant nucleoside analog prodrugs such as AraC, gemcitabine, and ddC. During the catalytic cycle the enzyme undergoes large conformational changes from open in the absence of substrates to closed in the presence of both phosphoryl donor and phosphoryl acceptor. Here we report the crystal structure of the substrate-free, open form of human UMP/CMP kinase. Comparison of the open structure with the closed state previously reported for the similar Dictyostelium discoideum UMP/CMP kinase reveals the conformational changes that occur upon substrate binding. We observe a classic example of induced fit where substrate-induced conformational changes in hinge residues result in rigid body movements of functional domains to form the catalytically competent state. In addition, a homology model of the human enzyme in the closed state based on the structure of D. discoideum UMP/CMP kinase aids to rationalize the substrate specificity of the human enzyme.

Received for publication, February 24, 2004 , and in revised form, May 14, 2004.

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

^* This work is supported by National Institutes of Health Grant AI46943 (to D. S.-P., N. S., and A. L.) and by funds from the Deutsche Forschungsgemeinschaft and the Max-Planck-Gesellschaft (to S. O. and M. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure and a movie.

^¶ To whom correspondence should be addressed: University of Illinois at Chicago, Dept. of Biochemistry and Molecular Genetics, 900 South Ashland Ave., Chicago, IL 60607. Tel.: 312-355-5029; Fax: 312-355-4535; E-mail: lavie{at}uic.edu.

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