期刊
SCIENCE
卷 333, 期 6041, 页码 459-462出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1204117
关键词
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资金
- National Science Council [99-2113-M-002-008-MY3, 99-2320-B-002-058-MY3, 100-2325-B-002-019]
- National Taiwan University College of Medicine [99R311001]
- National Health Research Institute [EX100-9939NI]
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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