|Title:||Structural basis of type II topoisomerase inhibition by the anticancer drug etoposide||Authors:||Wu C.-C.
|Issue Date:||2011||Journal Volume:||333||Journal Issue:||6041||Start page/Pages:||459-462||Source:||Science||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 TOP2b 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||metadata.dc.subject.other:||DNA topoisomerase (ATP hydrolysing); etoposide; cancer; chromosome; crystal structure; drug; enzyme activity; inhibition; molecular analysis; mutation; protein; topology; article; complex formation; crystal structure; DNA cleavage; drug binding; drug targeting; enzyme inhibition; gene mutation; human; molecular interaction; priority journal; Base Pairing; Catalytic Domain; Crystallography, X-Ray; DNA; DNA Topoisomerases, Type II; DNA-Binding Proteins; Drug Resistance, Neoplasm; Etoposide; Humans; Models, Molecular; Mutant Proteins; Mutation; Protein Multimerization; Protein Structure, Quaternary; Protein Structure, Tertiary; Structure-Activity Relationship; Topoisomerase II Inhibitors
|Appears in Collections:||微生物學科所|
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