title: On the structural basis and design guidelines for type II topoisomerase-targeting anticancer drugs.
abstract: Type II topoisomerases (Top2s) alter DNA topology via the formation of an enzyme-DNA adduct termed cleavage complex, which harbors a transient double-strand break in one DNA to allow the passage of another. Agents targeting human Top2s are clinically active anticancer drugs whose trapping of Top2-mediated DNA breakage effectively induces genome fragmentation and cell death. To understand the structural basis of this drug action, we previously determined the structure of human Top2 β-isoform forming a cleavage complex with the drug etoposide and DNA, and described the insertion of drug into DNA cleavage site and drug-induced decoupling of catalytic groups. By developing a post-crystallization drug replacement procedure that simplifies structural characterization of drug-stabilized cleavage complexes, we have extended the analysis toward other structurally distinct drugs, m-AMSA and mitoxantrone. Besides the expected drug intercalation, a switch in ribose puckering in the 3'-nucleotide of the cleavage site was robustly observed in the new structures, representing a new mechanism for trapping the Top2 cleavage complex. Analysis of drug-binding modes and the conformational landscapes of the drug-binding pockets provide rationalization of the drugs' structural-activity relationships and explain why Top2 mutants exhibit differential effects toward each drug. Drug design guidelines were proposed to facilitate the development of isoform-specific Top2-targeting anticancer agents.
authors.affiliation: Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 100, Taiwan, Institute of Biochemistry, College of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan, Department and Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan and Center for Biotechnology, National Taiwan University, Taipei 106, Taiwan.
authors.forename: Chyuan-Chuan
authors.initials: CC
authors.lastname: Wu
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Li
authors.forename: Ying-Ren
authors.initials: YR
authors.lastname: Wang
authors.forename: Tsai-Kun
authors.initials: TK
authors.lastname: Li
authors.forename: Nei-Li
authors.initials: NL
authors.lastname: Chan
mesh_terms: D000677:Amsacrine / Q000737:chemistry; D000951:Antigens, Neoplasm / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D004250:DNA Topoisomerases, Type II / Q000737:chemistry*; D004268:DNA-Binding Proteins / Q000737:chemistry*; D015195:Drug Design; D017408:Guidelines as Topic; D006801:Humans; D008942:Mitoxantrone / Q000737:chemistry; D008958:Models, Molecular; D000075223:Poly-ADP-Ribose Binding Proteins; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; D008942:Mitoxantrone; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human
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