TITLE

Structure of vaccinia virus thymidine kinase in complex with dTTP: insights for drug design

AUTHOR(S)
El Omari, Kamel; Solaroli, Nicola; Karlsson, Anna; Balzarini, Jan; Stammers, David K.
PUB. DATE
January 2006
SOURCE
BMC Structural Biology;2006, Vol. 6, p22
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Background: Development of countermeasures to bioterrorist threats such as those posed by the smallpox virus (variola), include vaccination and drug development. Selective activation of nucleoside analogues by virus-encoded thymidine (dThd) kinases (TK) represents one of the most successful strategies for antiviral chemotherapy as demonstrated for anti-herpes drugs. Vaccinia virus TK is a close orthologue of variola TK but also shares a relatively high sequence identity to human type 2 TK (hTK), thus achieving drug selectivity relative to the host enzyme is challenging. Results: In order to identify any differences compared to hTK that may be exploitable in drug design, we have determined the crystal structure of VVTK, in complex with thymidine 5'- triphosphate (dTTP). Although most of the active site residues are conserved between hTK and VVTK, we observe a difference in conformation of residues Asp-43 and Arg-45. The equivalent residues in hTK hydrogen bond to dTTP, whereas in subunit D of VVTK, Asp-43 and Arg-45 adopt a different conformation preventing interaction with this nucleotide. Asp-43 and Arg-45 are present in a flexible loop, which is disordered in subunits A, B and C. The observed difference in conformation and flexibility may also explain the ability of VVTK to phosphorylate (South)- methanocarbathymine whereas, in contrast, no substrate activity with hTK is reported for this compound. Conclusion: The difference in conformation for Asp-43 and Arg-45 could thus be used in drug design to generate VVTK/Variola TK-selective nucleoside analogue substrates and/or inhibitors that have lower affinity for hTK.
ACCESSION #
29323581

 

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