title: Structural basis of type II topoisomerase inhibition by the anticancer drug etoposide.
abstract: 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 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.
authors.affiliation: Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei City 100, Taiwan.
authors.forename: Chyuan-Chuan
authors.initials: CC
authors.lastname: Wu
authors.forename: Tsai-Kun
authors.initials: TK
authors.lastname: Li
authors.forename: Lynn
authors.initials: L
authors.lastname: Farh
authors.forename: Li-Ying
authors.initials: LY
authors.lastname: Lin
authors.forename: Te-Sheng
authors.initials: TS
authors.lastname: Lin
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Yu
authors.forename: Tien-Jui
authors.initials: TJ
authors.lastname: Yen
authors.forename: Chia-Wang
authors.initials: CW
authors.lastname: Chiang
authors.forename: Nei-Li
authors.initials: NL
authors.lastname: Chan
mesh_terms: D020029:Base Pairing; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D004268:DNA-Binding Proteins; D050505:Mutant Proteins; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D004247:DNA; D004250:DNA Topoisomerases, Type II