Structural basis for the specificity of thymidylate kinases from human pathogens: implications for nucleotide analogues activation.
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 A crystal structure of the thymidylate kinase bound to this compound now gives the structural basis for its specific molecular recognition.
Meyer
Philippe
P
Laboratoire d'Enzymologie et Biochimie Structurales, CNRS UPR3082, 91198 Gif-sur-yvette, France. meyer@lebs.cnrs-gif.fr
Caillat
Christophe
C
Topalis
Dimitri
D
Balzarini
Jan
J
Deville-Bonne
Dominique
D
D003856:Deoxyuracil Nucleotides / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D009703:Nucleoside-Phosphate Kinase / Q000737:chemistry* / Q000378:metabolism; D013379:Substrate Specificity; D014616:Vaccinia virus / Q000201:enzymology*
D003856:Deoxyuracil Nucleotides; C039764:5-(2-bromovinyl)-2'-deoxyuridylate; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase