PDBsum entry 4j3n

Isomerase/DNA

PDB id: 4j3n

Contents

Protein chains

666 a.a.

DNA/RNA

Metals

_MG ×7

Waters ×703

References listed in PDB file

Key reference

• Title: On the structural basis and design guidelines for type ii topoisomerase-Targeting anticancer drugs.
• Authors: C.C.Wu, Y.C.Li, Y.R.Wang, T.K.Li, N.L.Chan.
• Ref.: Nucleic Acids Res, 2013, 41, 10630-10640. [DOI no: 10.1093/nar/gkt828]
• PubMed id: 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 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.