PDBsum entry 4j3n

Isomerase/DNA

PDB id: 4j3n

Contents

Protein chains

666 a.a.

DNA/RNA

Metals

_MG ×7

Waters ×703

PDB id:

4j3n

Name:

Isomerase/DNA

Title:

Human topoisomerase iibeta in complex with DNA

Structure:

DNA topoisomerase 2-beta. Chain: a, b. Fragment: htop2beta cleavage core, unp residues 450-1206. Synonym: DNA topoisomerase ii, beta isozyme. Engineered: yes. DNA (5'-d(p Ap Gp Cp Cp Gp Ap Gp C)-3'). Chain: c, e. Engineered: yes. DNA (5'-d(p Tp Gp Cp Ap Gp Cp Tp Cp Gp Gp Cp T)-3').

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: top2b. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: the oligonucleotide sequence 5'-agccgagctgcagctcggct- 3' was ordered from viogene..

Resolution:

2.30Å R-factor: 0.178 R-free: 0.218

Authors:

C.C.Wu,T.K.Li,Y.C.Li,N.L.Chan

Key ref:

C.C.Wu et al. (2013). On the structural basis and design guidelines for type II topoisomerase-targeting anticancer drugs. Nucleic Acids Res, 41, 10630-10640. PubMed id: 24038465 DOI: 10.1093/nar/gkt828

Date:

06-Feb-13 Release date: 02-Oct-13

Protein chains

Q02880  (TOP2B_HUMAN) -  DNA topoisomerase 2-beta from Homo sapiens

Seq: 1626 a.a.

Struc: 666 a.a.

DNA/RNA chains

A-G-C-C-G-A-G-C 8 bases

T-G-C-A-G-C-T-C-G-G-C-T 12 bases

A-G-C-C-G-A-G-C 8 bases

T-G-C-G-C-T-C-G-G-C-T 11 bases

Enzyme reactions

• Enzyme class: E.C.5.6.2.2 - Dna topoisomerase (ATP-hydrolyzing).

DOI no: 10.1093/nar/gkt828

Nucleic Acids Res 41:10630-10640 (2013)

PubMed id: 24038465

On the structural basis and design guidelines for type II topoisomerase-targeting anticancer drugs.

C.C.Wu, Y.C.Li, Y.R.Wang, T.K.Li, N.L.Chan.

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.