On the structural basis and design guidelines for type II topoisomerase-targeting anticancer drugs.
Nucleic Acids Res
; 41(22): 10630-40, 2013 Dec.
Article
in En
| MEDLINE
| ID: mdl-24038465
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 ß-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.
Full text:
1
Database:
MEDLINE
Main subject:
DNA Topoisomerases, Type II
/
DNA-Binding Proteins
/
Topoisomerase II Inhibitors
/
Antigens, Neoplasm
/
Antineoplastic Agents
Type of study:
Guideline
Limits:
Humans
Language:
En
Journal:
Nucleic Acids Res
Year:
2013
Type:
Article
Affiliation country:
Taiwan