Cadmium(II) inhibition of human uracil-DNA glycosylase by catalytic water supplantation.
Cadmium(II) inhibition of human uracil-DNA glycosylase by catalytic water supplantation.
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DOI：
10.1038/srep39137
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发表时间：
2016-12-15
影响因子：
4.6
通讯作者：
Guliaev AB
中科院分区：
文献类型：
--
作者：
Gokey T;Hang B;Guliaev AB
已知有毒金属会抑制DNA修复，但抑制的潜在机制仍不完全清楚。DNA修复酶如人尿嘧啶-DNA糖基化酶（hUNG）执行碱基切除修复（BER）途径中的初始步骤。在这项工作中，我们发现镉[Cd（II）]，一种已知的人类致癌物质，在100 μM时抑制hUNG的所有活性。基于2 μs平衡、1.6 μs转向分子动力学（SMD）和QM/MM MD的计算分析确定Cd（II）离子进入酶活性位点并与D145和H148形成紧密接触，有效地取代了通常在该位置发现的催化水。通过密度泛函理论（DFT）计算的几何精修表明，Cd（II）与D145，P146，H148和一个水分子形成四面体结构。这项工作首次报道了镉（II）抑制hUNG，这是由于取代的催化水结合的活性位点D145和H148残基。建议的金属结合位点现有的结构数据的比较表明，D145：H148遵循一般的金属结合基序有利于镉（II）。所确定的基序提供了对其他DNA修复酶和糖基化酶的金属抑制的结构见解。
Toxic metals are known to inhibit DNA repair but the underlying mechanisms of inhibition are still not fully understood. DNA repair enzymes such as human uracil-DNA glycosylase (hUNG) perform the initial step in the base excision repair (BER) pathway. In this work, we showed that cadmium [Cd(II)], a known human carcinogen, inhibited all activity of hUNG at 100 μM. Computational analyses based on 2 μs equilibrium, 1.6 μs steered molecular dynamics (SMD), and QM/MM MD determined that Cd(II) ions entered the enzyme active site and formed close contacts with both D145 and H148, effectively replacing the catalytic water normally found in this position. Geometry refinement by density functional theory (DFT) calculations showed that Cd(II) formed a tetrahedral structure with D145, P146, H148, and one water molecule. This work for the first time reports Cd(II) inhibition of hUNG which was due to replacement of the catalytic water by binding the active site D145 and H148 residues. Comparison of the proposed metal binding site to existing structural data showed that D145:H148 followed a general metal binding motif favored by Cd(II). The identified motif offered structural insights into metal inhibition of other DNA repair enzymes and glycosylases.
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