Summary
PDB 4G0V deposited: 2012-07-10 modified: 2013-10-02
Title Human topoisomerase iibeta in complex with DNA and mitoxantrone
Authors Chan, N.L., Li, T.K., Li, Y.C., Wang, Y.R., Wu, C.C.
Method X-RAY DIFFRACTION
Structure factors resolution 2.548 rfactor 0.1608 rfree 0.206
DPI 0.46 theoretical min: 0.30
Related PDB Entries 4G0U 4G0W 4J3N
Citations

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.

Nucleic Acids Res. 2013 Dec; (22):- doi:10.1093/nar/gkt828

Cross References
Database source Identifier Description
PubMed 24038465 NARHAD
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
4G0V/1 4G0V 1 hexamer 0 6 8 11194