Structural Basis of Type II Topoisomerase Inhibition by the Anticancer Drug Etoposide
Structural Basis of Type II Topoisomerase Inhibition by the Anticancer Drug Etoposide
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DOI：
10.1126/science.1204117
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发表时间：
2011-07-22
期刊：
影响因子：
56.9
通讯作者：
Chan, Nei-Li
中科院分区：
文献类型：
--
作者：
Wu, Chyuan-Chuan;Li, Tsai-Kun;Chan, Nei-Li
II 型拓扑异构酶 (TOP2) 通过瞬时切割 DNA 双链体的两条链，形成切割复合物，通过该复合物运输另一个 DNA 片段，从而解决 DNA 的拓扑问题。几种广泛使用的抗癌药物会增加 TOP2 裂解复合物的数量，从而导致 TOP2 介导的染色体 DNA 断裂和癌细胞死亡。我们展示了与 DNA 和抗癌药物依托泊苷复合的人 TOP2 β 大片段的晶体结构，以揭示药物诱导的裂解复合物稳定的结构细节。蛋白质、DNA 和药物之间的相互作用解释了依托泊苷衍生物的构效关系和耐药突变的分子基础。蛋白质-药物相互作用的分析提供了适用于开发异构体特异性 TOP2 靶向策略的信息。
Type II topoisomerases (TOP2s) resolve the topological problems of DNA by transiently cleaving both strands of a DNA duplex to form a cleavage complex through which another DNA segment can be transported. Several widely prescribed anticancer drugs increase the population of TOP2 cleavage complex, which leads to TOP2-mediated chromosome DNA breakage and death of cancer cells. We present the crystal structure of a large fragment of human TOP2 beta complexed to DNA and to the anticancer drug etoposide to reveal structural details of drug-induced stabilization of a cleavage complex. The interplay between the protein, the DNA, and the drug explains the structure-activity relations of etoposide derivatives and the molecular basis of drug-resistant mutations. The analysis of protein-drug interactions provides information applicable for developing an isoform-specific TOP2-targeting strategy.