On the structural basis and design guidelines for type II topoisomerase-targeting anticancer drugs

Chyuan Chuan Wu, Yi Ching Li, Ying Ren Wang, Tsai Kun Li, Nei Li Chan

研究成果: Article同行評審

100 引文 斯高帕斯(Scopus)

摘要

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.

原文English
頁(從 - 到)10630-10640
頁數11
期刊Nucleic acids research
41
發行號22
DOIs
出版狀態Published - 2013 十二月

All Science Journal Classification (ASJC) codes

  • 遺傳學

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