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|標題:||Structural Basis of Type II Topoisomerase Inhibition by the Anticancer Drug Etoposide||作者:||Wu, C.C.
|關鍵字:||dna topoisomerases;cleavage;cancer;enzyme;alpha;beta;substituents;chemotherapy;perspective;resistance||Project:||Science||期刊/報告no：:||Science, Volume 333, Issue 6041, Page(s) 459-462.||摘要:||
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.
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