4J3N

Human Topoisomerase Iibeta in complex with DNA


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.178 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

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

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

(2013) Nucleic Acids Res 41: 10630-10640

  • DOI: https://doi.org/10.1093/nar/gkt828
  • Primary Citation of Related Structures:  
    4G0U, 4G0V, 4G0W, 4J3N

  • PubMed 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.


  • Organizational Affiliation

    Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 100, Taiwan, Institute of Biochemistry, College of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan, Department and Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan and Center for Biotechnology, National Taiwan University, Taipei 106, Taiwan.


Macromolecules

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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
DNA topoisomerase 2-beta
A, B
803Homo sapiensMutation(s): 0 
Gene Names: TOP2B
EC: 5.99.1.3
UniProt & NIH Common Fund Data Resources
Find proteins for Q02880 (Homo sapiens)
Explore Q02880 
Go to UniProtKB:  Q02880
PHAROS:  Q02880
GTEx:  ENSG00000077097 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ02880
Sequence Annotations
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  • Reference Sequence

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Entity ID: 2
MoleculeChains LengthOrganismImage
DNA (5'-D(P*AP*GP*CP*CP*GP*AP*GP*C)-3')
C, E
8N/A
Sequence Annotations
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  • Reference Sequence

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Entity ID: 3
MoleculeChains LengthOrganismImage
DNA (5'-D(P*TP*GP*CP*AP*GP*CP*TP*CP*GP*GP*CP*T)-3')
D, F
12N/A
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.178 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 79.953α = 90
b = 176.368β = 112.06
c = 94.225γ = 90
Software Package:
Software NamePurpose
Blu-Icedata collection
PHENIXmodel building
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-10-02
    Type: Initial release
  • Version 1.1: 2014-03-19
    Changes: Database references
  • Version 1.2: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description