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J. Biol. Chem., Vol. 279, Issue 34, 35479-35485, August 20, 2004

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Crystal Structure of Bacillus subtilis Guanine Deaminase

THE FIRST DOMAIN-SWAPPED STRUCTURE IN THE CYTIDINE DEAMINASE SUPERFAMILY^*

Shwu-Huey Liaw¶||, Yu-Jui Chang**, Cheng-Tsung Lai, Hui-Chuan Chang, and Gu-Gang Chang

From the Structural Biology Program, Faculty of Life Science, ^**Institute of Biotechnology in Medicine, and Institute of Genetics, National Yang-Ming University, Taipei 11221, Taiwan, and the ^¶Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 11217, Taiwan

Guanine deaminase, a key enzyme in the nucleotide metabolism, catalyzes the hydrolytic deamination of guanine into xanthine. The crystal structure of the 156-residue guanine deaminase from Bacillus subtilis has been solved at 1.17-Å resolution. Unexpectedly, the C-terminal segment is swapped to form an intersubunit active site and an intertwined dimer with an extensive interface of 3900 Ų per monomer. The essential zinc ion is ligated by a water molecule together with His⁵³, Cys⁸³, and Cys⁸⁶. A transition state analog was modeled into the active site cavity based on the tightly bound imidazole and water molecules, allowing identification of the conserved deamination mechanism and specific substrate recognition by Asp¹¹⁴ and Tyr^156'. The closed conformation also reveals that substrate binding seals the active site entrance, which is controlled by the C-terminal tail. Therefore, the domain swapping has not only facilitated the dimerization but has also ensured specific substrate recognition. Finally, a detailed structural comparison of the cytidine deaminase superfamily illustrates the functional versatility of the divergent active sites found in the guanine, cytosine, and cytidine deaminases and suggests putative specific substrate-interacting residues for other members such as dCMP deaminases.

Received for publication, May 12, 2004 , and in revised form, June 2, 2004.

^* This study was supported by National Science Council Grant NSC 92-2320-B-010-071. The synchrotron radiation experiments were performed at the National Synchrotron Radiation Research Center, Taiwan, the Photon Factory, Tsukuba, Japan, and the SPring-8, Sayo, Japan. 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 atomic coordinates and structure factors (code 1WKQ) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^|| To whom correspondence should be addressed. Tel.: 886-2-2826-7278; Fax: 886-2-2820-2449; E-mail: shliaw{at}ym.edu.tw.

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