The soluble metal-binding domain of the copper transporter ATP7B binds and detoxifies cisplatin.
The soluble metal-binding domain of the copper transporter ATP7B binds and detoxifies cisplatin.
复制标题
DOI：
10.1042/bj20081359
复制
发表时间：
2009-04-01
期刊：
影响因子：
--
通讯作者：
Dmitriev OY
中科院分区：
文献类型：
--
作者：
Dolgova NV;Olson D;Lutsenko S;Dmitriev OY
肝豆状核变性ATP酶（ATP 7 B）与癌细胞对顺铂的耐药性有关。在本研究中，我们使用细菌培养物中的简单体内测定，证明ATP 7 B可以通过将药物隔离在其N-末端金属结合结构域中而不从细胞中挤出活性药物来赋予顺铂抗性。表达含有ATP 7 B（MBR 1 -4）的四个N-末端MBR（金属结合重复）的蛋白片段保护细胞免受顺铂的毒性作用。一个MBR 1 -4分子在MBR中的铜结合位点结合多达三个顺铂分子。本研究的结果表明，抑制ATP 7 B的酶活性可能不是对抗顺铂耐药的有效方法。相反，应该努力防止顺铂与蛋白质结合。
Wilson disease ATPase (ATP7B) has been implicated in the resistance of cancer cells to cisplatin. Using a simple in vivo assay in bacterial culture, in the present study we demonstrate that ATP7B can confer resistance to cisplatin by sequestering the drug in its N-terminal metal-binding domain without active drug extrusion from the cell. Expression of a protein fragment containing four N-terminal MBRs (metal-binding repeats) of ATP7B (MBR1–4) protects cells from the toxic effects of cisplatin. One MBR1–4 molecule binds up to three cisplatin molecules at the copper-binding sites in the MBRs. The findings of the present study suggest that suppressing enzymatic activity of ATP7B may not be an effective way of combating cisplatin resistance. Rather, the efforts should be directed at preventing cisplatin binding to the protein.