Tetrathiomolybdate induces dimerization of the metal-binding domain of ATPase and inhibits platination of the protein
Tetrathiomolybdate induces dimerization of the metal-binding domain of ATPase and inhibits platination of the protein
复制标题
四硫代钼酸盐诱导 ATP 酶金属结合结构域的二聚化并抑制蛋白质的铂化
DOI：
10.1038/s41467-018-08102-z
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发表时间：
2019-01-14
影响因子：
16.6
通讯作者：
Liu, Yangzhong
中科院分区：
文献类型：
--
作者：
Fang, Tiantian;Chen, Wanbiao;Liu, Yangzhong
四硫代钼酸盐（TM）在临床上通过靶向细胞铜流出蛋白ATP 7 B（WLN）用于治疗威尔逊病。有趣的是，TM和WLN都与顺铂（一种广泛使用的抗癌药物）的疗效相关。在这里，我们表明，TM诱导二聚化的金属结合域的ATP 7 B（WLN 4）通过一个独特的硫桥连的Mo 2S 6 O2簇。TM从Cu-WLN 4中排出铜离子并形成无铜二聚体。Mo与WLN 4的半胱氨酸残基的结合抑制蛋白质的铂化。与多结构域蛋白的反应表明，TM也可以连接在同一分子中的两个结构域，形成Mo桥分子内交联。这些结果提供了结构和化学洞察TM对ATP酶的作用机制，并揭示了TM减弱铜外排蛋白介导的顺铂耐药性的分子机制。
Tetrathiomolybdate (TM) is used in the clinic for the treatment of Wilson's disease by targeting the cellular copper efflux protein ATP7B (WLN). Interestingly, both TM and WLN are associated with the efficacy of cisplatin, a widely used anticancer drug. Herein, we show that TM induces dimerization of the metal-binding domain of ATP7B (WLN4) through a unique sulfur-bridged Mo2S6O2 cluster. TM expels copper ions from Cu-WLN4 and forms a copper-free dimer. The binding of Mo to cysteine residues of WLN4 inhibits platination of the protein. Reaction with multi-domain proteins indicates that TM can also connect two domains in the same molecule, forming Mo-bridged intramolecular crosslinks. These results provide structural and chemical insight into the mechanism of action of TM against ATPase, and reveal the molecular mechanism by which TM attenuates the cisplatin resistance mediated by copper efflux proteins.