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J. Biol. Chem., Vol. 278, Issue 27, 24680-24687, July 4, 2003

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Crystal Structure of Varicella Zoster Virus Thymidine Kinase^*

Louise E. Bird  , Jingshan Ren  , Alan Wright , Kris D. Leslie , Bart Degrève ¶, Jan Balzarini ¶ and David K. Stammers  ||

From the Division of Structural Biology, The Wellcome Trust Centre for Human Genetics, Henry Wellcome Building of Genomic Medicine, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7BN, United Kingdom and ^¶Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium

Herpes virus thymidine kinases are responsible for the activation of nucleoside antiviral drugs including (E)-5-(2-bromovinyl)-2'-deoxyuridine. Such viral thymidine kinases (tk), beside having a broader substrate specificity compared with host cell enzymes, also show significant variation in nucleoside phosphorylation among themselves. We have determined the crystal structure of Varicella zoster virus (VZV, human herpes virus 3) thymidine kinase complexed with (E)-5-(2-bromovinyl)-2'-deoxyuridine 5'-monophosphate and ADP. Differences in the conformation of a loop region (residues 55–61) and the position of two -helices at the subunit interface of VZV-tk compared with the herpes simplex virus type 1 (human herpes virus 1) enzyme give rise to changes in the positioning of residues such as tyrosine 66 and glutamine 90, which hydrogen bond to the substrate in the active site. Such changes in combination with the substitution in VZV-tk of two phenylalanine residues (in place of a tyrosine and methionine), which sandwich the substrate pyrimidine ring, cause an alteration in the positioning of the base. The interaction of the (E)-5-(2-bromovinyl)-2'-deoxyuridine deoxyribose ring with the protein is altered by substitution of tyrosine 21 and phenylalanine 139 (analagous to herpes simplex virus type 1 histidine 58 and tyrosine 172), which may explain some of the differences in nucleoside sugar selectivity between both enzymes. The altered active site architecture may also account for the differences in the substrate activity of ganciclovir for the two thymidine kinases. These data should be of use in the design of novel antiherpes and antitumor drugs.

Received for publication, February 26, 2003 , and in revised form, April 8, 2003.

The atomic coordinates and structure factors (code 1OSN) 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 the "Belgische Federatie tegen kanker" (to J. B.), the Medical Research Council (to D. K. S.), and the European Commission Grant QLG1-CT-2001-01004 (to J. B. and D. K. 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.

Both authors contributed equally to this work.

^|| To whom correspondence should be addressed. Tel.: 44-1865-287565; Fax: 44-1865-287547; E-mail: Daves{at}strubi.ox.ac.uk.

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