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J. Biol. Chem., Vol. 279, Issue 32, 33806-33815, August 6, 2004

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Structure of Human MTH1, a Nudix Family Hydrolase That Selectively Degrades Oxidized Purine Nucleoside Triphosphates^*

From the ^aGraduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0101, Japan, ^bDivision of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Fukuoka 812-8582, Japan, ^cGraduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan, ^dUMR 216, CNRS and Institut Curie, 91405 Orsay, France, Laboratoire de Biocatalyse Faculte des Sciences et des Techniques, FRE2230, CNRS and Universite de Nantes, 2 Rue Houssiniere, 44322 Nantes Cedex 3 France, ^eGraduate School of Pharmaceutical Sciences, Kumamoto University, Oe-honmachi, Kumamoto 862-0973, Japan, ^fDivision of Chemistry, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan, ^hGraduate School of Integrated Science of Yokohama City University, Suehiro-cho 1-7-26, Tsurumi, Yokohama 230-0045, and ⁱGenomic Sciences Center, RIKEN, 1-7-22 Suehiro, Tsurumi, Yokohama, Kanagawa 230-0045, Japan

Oxygen radicals generated through normal cellular respiration processes can cause mutations in genomic and mitochondrial DNA. Human MTH1 hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP and 2-hydroxy-dATP, to monophosphates, thereby preventing the misincorporation of these oxidized nucleotides during replication. Here we present the solution structure of MTH1 solved by multidimensional heteronuclear NMR spectroscopy. The protein adopts a fold similar to that of Escherichia coli MutT, despite the low sequence similarity between these proteins outside the conserved Nudix motif. The substrate-binding pocket of MTH1, deduced from chemical shift perturbation experiments, is located at essentially the same position as in MutT; however, a pocket-forming helix is largely displaced in MTH1 (9 Å) such that the shape of the pocket differs between the two proteins. Detailed analysis of the pocket-forming residues enabled us to identify Asn³³ as one of the key residues in MTH1 for discriminating the oxidized form of purine, and mutation of this residue modifies the substrate specificity. We also show that MTH1 catalyzes hydrolysis of 8-oxo-dGTP through nucleophilic substitution of water at the -phosphate.

Received for publication, March 3, 2004 , and in revised form, April 13, 2004.

The atomic coordinates and structure factors (code 1IRY) 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 in part by grants-in-aid for scientific research (to M. S.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, by 21st Century COE Research from Ministry of Education, Culture, Sports, Science, and Technology of Japan (to M. M.), and by the Japan Science and Technology Agency (to M. M. and M. S.). 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.

^g To whom correspondence may be addressed. Tel.: 81-92-642-6800; Fax: 81-92-642-6791; E-mail: yusaku{at}bioreg.kyushu-u.ac.jp. ^j To whom correspondence may be addressed. Tel.: 81-45-508-7213; Fax: 81-45-508-7361; E-mail: shirakawa{at}tsurumi.yokohama-cu.ac.jp.

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