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- W2073301981 abstract "dUTPases are essential to eliminate dUTP for DNA integrity and provide dUMP for thymidylate biosynthesis. Mycobacterium tuberculosis apparently lacks any other thymidylate biosynthesis pathway, therefore dUTPase is a promising antituberculotic drug target. Crystal structure of the mycobacterial enzyme in complex with the isosteric substrate analog, α,β-imido-dUTP and Mg2+ at 1.5 Å resolution was determined that visualizes the full-length C-terminus, previously not localized. Interactions of a conserved motif important in catalysis, the Mycobacterium-specific five-residue-loop insert and C-terminal tetrapeptide could now be described in detail. Stacking of C-terminal histidine upon the uracil moiety prompted replacement with tryptophan. The resulting sensitive fluorescent sensor enables fast screening for binding of potential inhibitors to the active site. Kd for α,β-imido-dUTP binding to mycobacterial dUTPase is determined to be 10-fold less than for human dUTPase, which is to be considered in drug optimization. A robust continuous activity assay for kinetic screening is proposed." @default.
- W2073301981 created "2016-06-24" @default.
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- W2073301981 date "2008-08-01" @default.
- W2073301981 modified "2023-10-17" @default.
- W2073301981 title "Active site of mycobacterial dUTPase: Structural characteristics and a built-in sensor" @default.
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- W2073301981 doi "https://doi.org/10.1016/j.bbrc.2008.05.130" @default.
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