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.
Structure factors resolution 2.548 rfactor 0.1608 rfree 0.206
DPI 0.46 theoretical min: 0.30
Related PDB Entries 4G0U 4G0W 4J3N

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