Characterization of platinum anticancer drug protein-binding sites using a top-down mass spectrometric approach
Characterization of platinum anticancer drug protein-binding sites using a top-down mass spectrometric approach
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DOI：
10.1021/ic702236m
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发表时间：
2008-01-07
影响因子：
4.6
通讯作者：
Dyson, Paul J.
中科院分区：
文献类型：
--
作者：
Hartinger, Christian G.;Tsybin, Yury O.;Dyson, Paul J.
本文介绍了一项原理验证性研究，该研究采用自上而下的电喷雾电离傅里叶变换离子回旋共振质谱方法来表征铂类抗癌药物顺铂、反铂和奥沙利铂在泛素上的主要结合位点。通过采用不同的裂解技术，发现顺铂和奥沙利铂的结合位点位于含N端甲硫氨酸的泛素片段上，而反铂则被观察到结合在（19）脯氨酸 - 丝氨酸 - 天冬氨酸 - 苏氨酸 - 异亮氨酸 - 谷氨酸（24）上。就（去）活化、转运、排泄等方面而言，与蛋白质的结合对于金属药物的作用方式具有特别重要的意义。据我们所知，这是第一项关于过渡金属抗癌药物蛋白质结合位点表征的自上而下的质谱研究，并展示了所应用技术在研究金属药物 - 蛋白质相互作用方面的潜力。
A proof-of -principle study on the application of a top-down electrospray ionization Fourier transform ion cyclotron resonance mass spectrometric approach for characterization of the primary binding sites of the platinum anticancer agents cisplatin, transplatin, and oxaliplatin on ubiquitin is presented. Through employment of different fragmentation techniques, the binding sites of cisplatin and oxaliplatin were found at N-terminal methionine-containing ubiquitin fragments, while transplatin was observed to be attached to (19)Pro-Ser-Asp-Thr-IIe-Glu(24). The binding to proteins is of particular relevance for the mode of action of metallodrugs with regard to (de)activation, transport, excretion, etc. To the best of our knowledge, this is the first top-down mass spectrometric study on the protein binding site characterization of transition-metal anticancer agents and demonstrates the potential of the applied technique for investigating metal drug-protein interactions.