Structural Basis of Type II Topoisomerase Inhibition by the Anticancer Drug Etoposide
2011; American Association for the Advancement of Science; Volume: 333; Issue: 6041 Linguagem: Inglês
10.1126/science.1204117
ISSN1095-9203
AutoresChyuan-Chuan Wu, Tsai‐Kun Li, Lynn Farh, Li‐Ying Lin, Te‐Sheng Lin, Yu‐Jen Yu, Tien-Jui Yen, Chia-Wang Chiang, Nei‐Li Chan,
Tópico(s)Synthesis and biological activity
ResumoType 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 TOP2β 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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