1PVG

Crystal Structure of the ATPase region of Saccharomyces Cerevisiae topoisomerase II


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.209 

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This is version 1.3 of the entry. See complete history


Literature

Structure of the topoisomerase II ATPase region and its mechanism of inhibition by the chemotherapeutic agent ICRF-187

Classen, S.Olland, S.Berger, J.M.

(2003) Proc Natl Acad Sci U S A 100: 10629-10634

  • DOI: https://doi.org/10.1073/pnas.1832879100
  • Primary Citation of Related Structures:  
    1PVG, 1QZR

  • PubMed Abstract: 

    Type IIA topoisomerases both manage the topological state of chromosomal DNA and are the targets of a variety of clinical agents. Bisdioxopiperazines are anticancer agents that associate with ATP-bound eukaryotic topoisomerase II (topo II) and convert the enzyme into an inactive, salt-stable clamp around DNA. To better understand both topo II and bisdioxopiperazine function, we determined the structures of the adenosine 5'-[beta,gamma-imino]-triphosphate-bound yeast topo II ATPase region (ScT2-ATPase) alone and complexed with the bisdioxopiperazine ICRF-187. The drug-free form of the protein is similar in overall fold to the equivalent region of bacterial gyrase but unexpectedly displays significant conformational differences. The ternary drug-bound complex reveals that ICRF-187 acts by an unusual mechanism of inhibition in which the drug does not compete for the ATP-binding pocket, but bridges and stabilizes a transient dimer interface between two ATPase protomers. Our data explain why bisdioxopiperazines target ATP-bound topo II, provide a structural rationale for the effects of certain drug-resistance mutations, and point to regions of bisdioxopiperazines that might be modified to improve or alter drug specificity.


  • Organizational Affiliation

    Department of Molecular and Cell Biology, 237 Hildebrand Hall, University of California, Berkeley, CA 94720-3206, USA.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
DNA topoisomerase II
A, B
418Saccharomyces cerevisiaeMutation(s): 10 
Gene Names: TOP2
EC: 5.99.1.3
UniProt
Find proteins for P06786 (Saccharomyces cerevisiae (strain ATCC 204508 / S288c))
Explore P06786 
Go to UniProtKB:  P06786
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP06786
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
MSE
Query on MSE
A, B
L-PEPTIDE LINKINGC5 H11 N O2 SeMET
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.209 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.456α = 90
b = 71.081β = 90
c = 216.132γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
Blu-Icedata collection
SCALEPACKdata scaling
SOLVEphasing
RESOLVEphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2003-08-26
    Type: Initial release
  • Version 1.1: 2008-04-29
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Advisory, Version format compliance
  • Version 1.3: 2017-10-11
    Changes: Refinement description