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KINETICS AND CRYSTAL STRUCTURE OF THE HERPES SIMPLEX VIRUS TYPE 1 THYMIDINE KINASE INTERACTING WITH (SOUTH)-METHANOCARBA-THYMIDINEKINETICS AND CRYSTAL STRUCTURE OF THE HERPES SIMPLEX VIRUS TYPE 1 THYMIDINE KINASE INTERACTING WITH (SOUTH)-METHANOCARBA-THYMIDINE
Structural highlights
FunctionKITH_HHV11 In latent infection, may allow the virus to be reactivated and to grow in cells lacking a high concentration of phosphorylated nucleic acid precursors, such as nerve cells that do not replicate their genome (By similarity). 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 PubMedTwo analogs of the natural nucleoside dT featuring a pseudosugar with fixed conformation in place of the deoxyribosyl residue (carbathymidine analogs) were biochemically and structurally characterized for their acceptance by both human cytosolic thymidine kinase isoenzyme 1 (hTK1) and herpes simplex virus type 1 thymidine kinase (HSV1 TK) and subsequently tested in cell proliferation assays. 3'-exo-Methanocarbathymidine ((South)-methanocarbathymidine (S)-MCT), which is a substrate for HSV1 TK, specifically inhibited growth of HSV1 TK-transduced human osteosarcoma cells with an IC(50) value in the range of 15 microM without significant toxicity toward both hTK1-negative (TK(-)) and non-transduced cells. 2'-exo-Methanocarbathymidine ((North)-methanocarbathymidine (N)-MCT), which is a weak substrate for hTK1 and a substantial one for HSV1 TK, induced a specific growth inhibition in HSV1 TK-transfected cells comparable to that of (S)-MCT and ganciclovir. A growth inhibition activity was also observed with (N)-MCT and ganciclovir in non-transduced cells in a cell line-dependent manner, whereas TK(-) cells were not affected. The presented 1.95-A crystal structure of the complex (S)-MCT.HSV1 TK explains both the more favorable binding affinity and catalytic turnover of (S)-MCT for HSV1 TK over the North analog. Additionally the plasticity of the active site of the enzyme is addressed by comparing the binding of (North)- and (South)-carbathymidine analogs. The presented study of these two potent candidate prodrugs for HSV1 TK gene-directed enzyme prodrug therapy suggests that (S)-MCT may be even safer to use than its North counterpart (N)-MCT. Biochemical and structural characterization of (South)-methanocarbathymidine that specifically inhibits growth of herpes simplex virus type 1 thymidine kinase-transduced osteosarcoma cells.,Schelling P, Claus MT, Johner R, Marquez VE, Schulz GE, Scapozza L J Biol Chem. 2004 Jul 30;279(31):32832-8. Epub 2004 May 25. PMID:15163659[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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