© 2009 Oxford University Press
This article appears in the following Nucleic Acid Symposium Series issue: The 6th International Symposium on Nucleic Acids Chemistry (36th Symposium on Nucleic Acids Chemistry) [View the issue table of contents]
Structural basis for the specificity of thymidylate kinases from human pathogens: implications for nucleotide analogues activation
1Laboratoire d'Enzymologie et Biochimie Structurales, CNRS UPR3082, 91198 Gif-sur-yvette, France, 2Université Paris 6, Laboratoire d’Enzymologie Moléculaire, CNRS FRE2852, 75345 Paris, France and 3Rega Institute for Medical Research, Minderbroedersstraat 10, B 3000 Leuven, Belgium
*Corresponding author. E-mail: meyer{at}lebs.cnrs-gif.fr
Abstract
Several human pathogens possess nucleoside or nucleotide kinases with large substrate specificity compared to their human counterparts. This phenomenon has been successfully exploited for the specific targeting of prodrugs such as Acyclovir against herpes virus. Combined structural and biochemical studies of these enzymes can thus provide essential information for the rational design of specific antimicrobial agents. Here we studied the structural basis for the specificity of a thymidylate kinase from the poxvirus family. Poxvirus thymidylate kinase has unusual substrate specificity and can accept bulky analogues such as 5-bromo-vinyl-dUMP (BVdUMP). The 2 Å crystal structure of the thymidylate kinase bound to this compound now gives the structural basis for its specific molecular recognition.