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J. Biol. Chem., Vol. 282, Issue 14, 10441-10448, April 6, 2007

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Structure and Function of the c-myc DNA-unwinding Element-binding Protein DUE-B^*

Michael Kemp, Brian Bae, John Paul Yu^¶, Maloy Ghosh, Michael Leffak¹, and Satish K. Nair^¶2

From the Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio 45435 and Department of Biochemistry and ^¶Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801

Local zones of easily unwound DNA are characteristic of prokaryotic and eukaryotic replication origins. The DNA-unwinding element of the human c-myc replication origin is essential for replicator activity and is a target of the DNA-unwinding element-binding protein DUE-B in vivo. We present here the 2.0Å crystal structure of DUE-B and complementary biochemical characterization of its biological activity. The structure corresponds to a dimer of the N-terminal domain of the full-length protein and contains many of the structural elements of the nucleotide binding fold. A single magnesium ion resides in the putative active site cavity, which could serve to facilitate ATP hydrolytic activity of this protein. The structure also demonstrates a notable similarity to those of tRNA-editing enzymes. Consistent with this structural homology, the N-terminal core of DUE-B is shown to display both D-aminoacyl-tRNA deacylase activity and ATPase activity. We further demonstrate that the C-terminal portion of the enzyme is disordered and not essential for dimerization. However, this region is essential for DNA binding in vitro and becomes ordered in the presence of DNA.

Received for publication, October 12, 2006 , and in revised form, January 18, 2007.

The atomic coordinates and structure factors (code 2OKV) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by the Elsa U. Pardee Foundation and Public Health Service Grant GM53819 (to M. L.) and American Cancer Society Grant 04-37 (to S. K. N.). 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.

¹ To whom correspondence may be addressed. Tel.: 937-775-3125; Fax: 775-775-3730; E-mail: michael.leffak{at}wright.edu. ² To whom correspondence may be addressed. Tel.: 217-333-2688; Fax: 217-244-5858; E-mail: snair{at}uiuc.edu.

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