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外文期刊>The biochemical journal
>Copper chaperone Atox1 interacts with the metal-binding domain of Wilson's disease protein in cisplatin detoxification
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Copper chaperone Atox1 interacts with the metal-binding domain of Wilson's disease protein in cisplatin detoxification
pHuman copper transporters ATP7B (Wilson9s disease protein) and ATP7A (Menkes9 disease protein) have been implicated in tumour resistance to cisplatin, a widely used anticancer drug. Cisplatin binds to the copper-binding sites in the N-terminal domain of ATP7B, and this binding may be an essential step of cisplatin detoxification involving copper ATPases. In the present study, we demonstrate that cisplatin and a related platinum drug carboplatin produce the same adduct following reaction with MBD2 [metal-binding domain (repeat) 2], where platinum is bound to the side chains of the cysteine residues in the CxxC copper-binding motif. This suggests the same mechanism for detoxification of both drugs by ATP7B. Platinum can also be transferred to MBD2 from copper chaperone Atox1, which was shown previously to bind cisplatin. Binding of the free cisplatin and reaction with the cisplatin-loaded Atox1 produce the same protein-bound platinum intermediate. Transfer of platinum along the copper-transport pathways in the cell may serve as a mechanism of drug delivery to its target in the cell nucleus, and explain tumour-cell resistance to cisplatin associated with the overexpression of copper transporters ATP7B and ATP7A./p
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机译:>人类铜转运蛋白ATP7B(Wilson9s病蛋白)和ATP7A(Menkes9病蛋白)与顺铂(一种广泛使用的抗癌药物)的抗药性有关。顺铂结合到ATP7B N末端结构域中的铜结合位点,这种结合可能是顺铂解毒过程中涉及铜ATP酶的重要步骤。在本研究中,我们证明顺铂和相关的铂药物卡铂在与MBD2 [金属结合结构域(重复)2]反应后产生相同的加合物,其中铂与CxxC铜中半胱氨酸残基的侧链结合结合基序。这表明ATP7B对两种药物进行解毒的机制相同。铂也可以从分子伴侣铜Atox1转移至MBD2,后者先前已证明可与顺铂结合。游离顺铂的结合以及与顺铂加载的Atox1的反应产生相同的蛋白质结合铂中间体。铂沿细胞中铜转运途径的转移可能是药物向细胞核中靶标传递的机制,并解释了肿瘤细胞对顺铂的耐药性与铜转运蛋白ATP7B和ATP7A的过表达有关。 p >
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