4G0V

Human topoisomerase iibeta in complex with DNA and mitoxantrone

Summary for 4G0V

• Entry DOI: 10.2210/pdb4g0v/pdb
• Related: 3QX3 4G0U 4G0W 4J3N
• Descriptor: DNA topoisomerase 2-beta, DNA (5'-D(P*AP*GP*CP*CP*GP*AP*GP*C)-3'), DNA (5'-D(P*TP*GP*CP*AP*GP*CP*TP*CP*GP*GP*CP*T)-3'), ... (6 entities in total)
• Functional Keywords: toprim domain, winged-helix domain, coiled-coil domain, dna-binding and cleavage, nucleus, isomerase-dna-isomerase inhibitor complex, isomerase/dna/isomerase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q02880
• Total number of polymer chains: 6
• Total formula weight: 197073.52

Authors

Wu, C.C.,Li, T.K.,Li, Y.C.,Chan, N.L. (deposition date: 2012-07-10, release date: 2013-07-17, Last modification date: 2024-10-30)

Primary citation

Wu, C.C.,Li, Y.C.,Wang, Y.R.,Li, T.K.,Chan, N.L.
On the structural basis and design guidelines for type II topoisomerase-targeting anticancer drugs
Nucleic Acids Res., 41:10630-10640, 2013

PubMed 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.

PubMed: 24038465
DOI: 10.1093/nar/gkt828

Experimental method

X-RAY DIFFRACTION (2.548 Å)