通过抗癌药物抑制铜贩运的机制和结构基础
Alessia Lasorsa1, Maria I Nardella1, Antonio Rosato1
1Department of Chemistry , University of Bari "Aldo Moro" , via Orabona, 4 , 70125 Bari , Italy.
Journal of the American Chemical Society
|July 9, 2019
概括
类药物如思因与Atox1-Cu (I) -Mnk1复合体结合而干扰铜运输. 这种相互作用会破坏铜的平衡,影响癌细胞的活力和迁移.
科学领域:
- 生物化学
- 金属蛋白化学
- 癌症治疗方法
背景情况:
- 铜 (Cu) 对于酶成熟,细胞增殖和血管生成至关重要,需要特定的蛋白质相互作用来进行运输.
- 铜伴奏体Atox1为ATP7a/Atp7b提供Cu (I),这对铜的调节和分泌至关重要.
- 铜转移涉及Atox1和Cu-ATPases之间的短暂的三坐标中间体,使用CxxC二醇基因.
研究的目的:
- 研究抗瘤药物与Atox1-Cu(I) - ATPase复合物的相互作用.
- 阐明药与铜运输蛋白结合的结构基础和功能后果.
主要方法:
- 使用溶液NMR和X射线结晶学对Atox1-Cu(I) -Mnk1-Pt(II) 添加物的结构性表征.
- 使用突变蛋白来评估不同结合配置的稳定性和反应性.
- 研究了金属离子 (Cu(I) 与Zn(II)) 和药物异构体 (cisplatin与transplatin) 对复合物形成的影响.
主要成果:
- 齐斯普拉丁和一个氧利普拉丁类似物与Atox1-Cu(I) -Mnk1复合物形成了动态稳定的添加物.
- 结构分析揭示了特定的结合配置,其中一个较不稳定,对Pt{II}更有反应性.
- 铜离子可以被保留在协调部位,但被释放到诸如谷类的生理类醇.
结论:
- 类药物特别向和稳定Atox1-Cu(I) - ATPase复合体,破坏铜的平衡.
- 对铜离子交换的干扰影响了癌细胞的活力和迁移.
- 这些发现突出了基化疗针对金属离子贩运的新型作用机制.
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