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首页> 外文期刊>Journal of Molecular Biology >Insights into Substrate Binding and Catalytic Mechanism of Human Tyrosyl-DNA Phosphodiesterase (Tdp1) from Vanadate and Tungstate-inhibited Structures.
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Insights into Substrate Binding and Catalytic Mechanism of Human Tyrosyl-DNA Phosphodiesterase (Tdp1) from Vanadate and Tungstate-inhibited Structures.

机译：从钒酸盐和钨酸盐抑制结构深入了解人酪氨酰-DNA磷酸二酯酶（Tdp1）的底物结合和催化机理。

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摘要

Tyrosyl-DNA phosphodiesterase (Tdp1) is a DNA repair enzyme that catalyzes the hydrolysis of a phosphodiester bond between a tyrosine residue and a DNA 3'-phosphate. The only known example of such a linkage in eukaryotic cells occurs normally as a transient link between a type IB topoisomerase and DNA. Thus human Tdp1 is thought to be responsible for repairing lesions that occur when topoisomerase I becomes stalled on the DNA in the cell. Tdp1 has also been shown to remove glycolate from single-stranded DNA containing a 3'-phosphoglycolate, suggesting a role for Tdp1 in repair of free-radical mediated DNA double-strand breaks. We report the three-dimensional structures of human Tdp1 bound to the phosphate transition state analogs vanadate and tungstate. Each structure shows the inhibitor covalently bound to His263, confirming that this residue is the nucleophile in the first step of the catalytic reaction. Vanadate in the Tdp1-vanadate structure has a trigonal bipyramidal geometry that mimics the transition state for hydrolysis of a phosphodiester bond, while Tdp1-tungstate displays unusual octahedral coordination. The presence of low-occupancy tungstate molecules along the narrow groove of the substrate binding cleft is suggestive evidence that this groove binds ssDNA. In both cases, glycerol from the cryoprotectant solution became liganded to the vanadate or tungstate inhibitor molecules in a bidentate 1,2-diol fashion. These structural models allow predictions to be made regarding the specific binding mode of the substrate and the mechanism of catalysis.
机译：酪氨酰-DNA磷酸二酯酶（Tdp1）是一种DNA修复酶，可催化酪氨酸残基和DNA 3'-磷酸之间的磷酸二酯键水解。真核细胞中这种连接的唯一已知实例通常是作为IB型拓扑异构酶与DNA之间的瞬时连接而发生的。因此，人们认为人类Tdp1负责修复拓扑异构酶I停滞在细胞DNA上时发生的病变。 Tdp1还显示可从含有3'-磷酸乙醇酸的单链DNA中去除乙醇酸，表明Tdp1在自由基介导的DNA双链断裂修复中具有重要作用。我们报告绑定到磷酸盐过渡态类似物钒酸盐和钨酸盐的人类Tdp1的三维结构。每个结构都显示出与His263共价结合的抑制剂，从而证实了该残基是催化反应第一步中的亲核试剂。 Tdp1-钒酸盐结构中的钒酸盐具有三角双锥几何形状，模仿了磷酸二酯键水解的过渡态，而Tdp1-钨酸盐显示出异常的八面体配位。沿底物结合裂隙的窄槽存在低占有率的钨酸盐分子，表明该槽结合了ssDNA。在这两种情况下，来自冷冻保护剂溶液的甘油都以双齿1,2-二醇的方式与钒酸盐或钨酸盐抑制剂分子配位。这些结构模型允许对底物的特异性结合模式和催化机理进行预测。

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