Wu C.-C.TSAI-KUN LIFarh L.Lin L.-Y.Lin T.-S.Yu Y.-J.Yen T.-J.Chiang C.-W.NEI-LI CHAN2020-02-062020-02-0620110036-8075https://www.scopus.com/inward/record.uri?eid=2-s2.0-79960676884&doi=10.1126%2fscience.1204117&partnerID=40&md5=66127b44228d3964c2cd8e2de9bb9db4https://scholars.lib.ntu.edu.tw/handle/123456789/454018Type 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.[SDGs]SDG3DNA 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 Inhibitorsjournal article10.1126/science.12041172-s2.0-79960676884