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標題: Structural Basis of Type II Topoisomerase Inhibition by the Anticancer Drug Etoposide
作者: Wu, C.C.
Li, T.K.
Farh, L.
Lin, L.Y.
Lin, T.S.
Yu, Y.J.
Yen, T.J.
Chiang, C.W.
Chan, N.L.
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.
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.
ISSN: 0036-8075
DOI: 10.1126/science.1204117
Appears in Collections:期刊論文

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