2j87

STRUCTURE OF VACCINIA VIRUS THYMIDINE KINASE IN COMPLEX WITH DTTP: INSIGHTS FOR DRUG DESIGN

spinqualitylabelsall models 2j87, resolution 3.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2j87 is a 4 chain structure with sequence from Vaccinia virus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: MG, TTP, ZN Activity: Thymidine kinase, with EC number 2.7.1.21 Resources: FirstGlance, OCA, RCSB, PDBsum Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed 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. Structure of vaccinia virus thymidine kinase in complex with dTTP: insights for drug design.,El Omari K, Solaroli N, Karlsson A, Balzarini J, Stammers DK BMC Struct Biol. 2006 Oct 24;6:22. PMID:17062140 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Thymidine kinase

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