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PDBsum entry 1qzr
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protein ligands metals Protein-protein interface(s) links
Isomerase PDB id
1qzr

 

 

 

 

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Contents
Protein chains
382 a.a. *
Ligands
ANP ×2
CDX
Metals
_MG ×2
Waters ×766
* Residue conservation analysis
PDB id:
1qzr
Name: Isomerase
Title: Crystal structure of the atpase region of saccharomyces cerevisiae topoisomerase ii bound to icrf-187 (dexrazoxane)
Structure: DNA topoisomerase ii. Chain: a, b. Fragment: n-terminal atpase region. Engineered: yes
Source: Saccharomyces cerevisiae. Baker's yeast. Organism_taxid: 4932. Gene: top2. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Dimer (from PQS)
Resolution:
1.90Å     R-factor:   0.199     R-free:   0.237
Authors: S.Classen,S.Olland,J.M.Berger
Key ref:
S.Classen et al. (2003). Structure of the topoisomerase II ATPase region and its mechanism of inhibition by the chemotherapeutic agent ICRF-187. Proc Natl Acad Sci U S A, 100, 10629-10634. PubMed id: 12963818 DOI: 10.1073/pnas.1832879100
Date:
17-Sep-03     Release date:   30-Sep-03    
Supersedes: 1q1d
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
P06786  (TOP2_YEAST) -  DNA topoisomerase 2 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1428 a.a.
382 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.5.6.2.2  - Dna topoisomerase (ATP-hydrolyzing).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

 

 
DOI no: 10.1073/pnas.1832879100 Proc Natl Acad Sci U S A 100:10629-10634 (2003)
PubMed id: 12963818  
 
 
Structure of the topoisomerase II ATPase region and its mechanism of inhibition by the chemotherapeutic agent ICRF-187.
S.Classen, S.Olland, J.M.Berger.
 
  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.
 
  Selected figure(s)  
 
Figure 2.
Fig. 2. (a) Stereo diagram of the ScT2-ATPase dimer. The GHKL and transducer domains are colored gold and orange, respectively. A 22-aa -hairpin unique to eukaryotic topo II is colored light blue. ICRF-187 is shown as blue spheres. All residues within 5 Å of the drug are colored green. ADPNP is shown as spheres and colored by atom. (b) Buried dimer surface area. This is a surface representation of a single protomer seen from the dimer interface, showing surfaces involved in dimer interactions. Distances between the surfaces of each protomer were calculated with GRASP (29) and range from 0 Å (white) to >7 Å (red). The ICRF-187-binding pocket sits in the middle of the primary dimer interface. 		Figure 4.
Fig. 4. Surface representation of ScT2-ATPase and E. coli GyrB dimers. Each molecule has one protomer colored dark gray (GHKL) and light gray (transducer), and one protomer colored gold (GHKL) and orange (transducer). A 22-aa insert specific to eukaryotic topo II is colored light blue.
 
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
23022727 B.H.Schmidt, N.Osheroff, and J.M.Berger (2012).
Structure of a topoisomerase II-DNA-nucleotide complex reveals a new control mechanism for ATPase activity.
  Nat Struct Mol Biol, 19, 1147-1154.
PDB code: 4gfh
22173432 Y.Pommier, and C.Marchand (2012).
Interfacial inhibitors: targeting macromolecular complexes.
  Nat Rev Drug Discov, 11, 25-36.  
21475246 C.S.McHenry (2011).
Breaking the rules: bacteria that use several DNA polymerase IIIs.
  EMBO Rep, 12, 408-414.  
21103609 F.P.Davis (2011).
Proteome-wide prediction of overlapping small molecule and protein binding sites using structure.
  Mol Biosyst, 7, 545-557.  
20870749 N.M.Baker, S.Weigand, S.Maar-Mathias, and A.Mondragón (2011).
Solution structures of DNA-bound gyrase.
  Nucleic Acids Res, 39, 755-766.  
22108601 S.M.Vos, E.M.Tretter, B.H.Schmidt, and J.M.Berger (2011).
All tangled up: how cells direct, manage and exploit topoisomerase function.
  Nat Rev Mol Cell Biol, 12, 827-841.  
19603203 C.E.Cassidy, and W.N.Setzer (2010).
Cancer-relevant biochemical targets of cytotoxic Lonchocarpus flavonoids: a molecular docking analysis.
  J Mol Model, 16, 311-326.  
  20703329 J.E.Deweese, and N.Osheroff (2010).
The use of divalent metal ions by type II topoisomerases.
  Metallomics, 2, 450-459.  
20127325 P.Xie (2010).
Dynamics of strand passage catalyzed by topoisomerase II.
  Eur Biophys J, 39, 1251-1259.  
21062409 W.M.FitzPatrick, N.G.Dervisis, and B.E.Kitchell (2010).
Safety of concurrent administration of dexrazoxane and doxorubicin in the canine cancer patient.
  Vet Comp Oncol, 8, 273-282.  
20855424 Y.Li, Y.Luan, X.Qi, M.Li, L.Gong, X.Xue, X.Wu, Y.Wu, M.Chen, G.Xing, J.Yao, and J.Ren (2010).
Emodin triggers DNA double-strand breaks by stabilizing topoisomerase II-DNA cleavage complexes and by inhibiting ATP hydrolysis of topoisomerase II.
  Toxicol Sci, 118, 435-443.  
19377505 J.L.Nitiss (2009).
DNA topoisomerase II and its growing repertoire of biological functions.
  Nat Rev Cancer, 9, 327-337.  
19377506 J.L.Nitiss (2009).
Targeting DNA topoisomerase II in cancer chemotherapy.
  Nat Rev Cancer, 9, 338-350.  
19059997 J.Roca (2009).
Topoisomerase II: a fitted mechanism for the chromatin landscape.
  Nucleic Acids Res, 37, 721-730.  
19098900 K.Luo, J.Yuan, J.Chen, and Z.Lou (2009).
Topoisomerase IIalpha controls the decatenation checkpoint.
  Nat Cell Biol, 11, 204-210.  
19071108 L.M.Oppegard, A.V.Ougolkov, D.N.Luchini, R.A.Schoon, J.R.Goodell, H.Kaur, D.D.Billadeau, D.M.Ferguson, and H.Hiasa (2009).
Novel acridine-based compounds that exhibit an anti-pancreatic cancer activity are catalytic inhibitors of human topoisomerase II.
  Eur J Pharmacol, 602, 223-229.  
19494182 M.Johnson, H.H.Phua, S.C.Bennett, J.M.Spence, and C.J.Farr (2009).
Studying vertebrate topoisomerase 2 function using a conditional knockdown system in DT40 cells.
  Nucleic Acids Res, 37, e98.  
19230795 M.T.Lee, and J.Bachant (2009).
SUMO modification of DNA topoisomerase II: trying to get a CENse of it all.
  DNA Repair (Amst), 8, 557-568.  
19128485 P.Chène, J.Rudloff, J.Schoepfer, P.Furet, P.Meier, Z.Qian, J.M.Schlaeppi, R.Schmitz, and T.Radimerski (2009).
Catalytic inhibition of topoisomerase II by a novel rationally designed ATP-competitive purine analogue.
  BMC Chem Biol, 9, 1.  
19155278 T.R.Collins, G.G.Hammes, and T.S.Hsieh (2009).
Analysis of the eukaryotic topoisomerase II DNA gate: a single-molecule FRET and structural perspective.
  Nucleic Acids Res, 37, 712-720.  
18755053 A.J.Schoeffler, and J.M.Berger (2008).
DNA topoisomerases: harnessing and constraining energy to govern chromosome topology.
  Q Rev Biophys, 41, 41.  
18403371 F.Mueller-Planitz, and D.Herschlag (2008).
Coupling between ATP binding and DNA cleavage by DNA topoisomerase II: A unifying kinetic and structural mechanism.
  J Biol Chem, 283, 17463-17476.  
17681352 A.K.McClendon, and N.Osheroff (2007).
DNA topoisomerase II, genotoxicity, and cancer.
  Mutat Res, 623, 83-97.  
17519947 D.Lebrecht, A.Geist, U.P.Ketelsen, J.Haberstroh, B.Setzer, and U.A.Walker (2007).
Dexrazoxane prevents doxorubicin-induced long-term cardiotoxicity and protects myocardial mitochondria from genetic and functional lesions in rats.
  Br J Pharmacol, 151, 771-778.  
17355868 L.Costenaro, J.G.Grossmann, C.Ebel, and A.Maxwell (2007).
Modular structure of the full-length DNA gyrase B subunit revealed by small-angle X-ray scattering.
  Structure, 15, 329-339.  
17298034 R.P.Bender, A.J.Ham, and N.Osheroff (2007).
Quinone-induced enhancement of DNA cleavage by human topoisomerase IIalpha: adduction of cysteine residues 392 and 405.
  Biochemistry, 46, 2856-2864.  
17516663 R.P.Bender, and N.Osheroff (2007).
Mutation of cysteine residue 455 to alanine in human topoisomerase IIalpha confers hypersensitivity to quinones: enhancing DNA scission by closing the N-terminal protein gate.
  Chem Res Toxicol, 20, 975-981.  
16926632 B.B.Hasinoff, X.Wu, J.C.Yalowich, V.Goodfellow, R.S.Laufer, O.Adedayo, and G.I.Dmitrienko (2006).
Kinamycins A and C, bacterial metabolites that contain an unusual diazo group, as potential new anticancer agents: antiproliferative and cell cycle effects.
  Anticancer Drugs, 17, 825-837.  
16505102 C.Marchand, S.Antony, K.W.Kohn, M.Cushman, A.Ioanoviciu, B.L.Staker, A.B.Burgin, L.Stewart, and Y.Pommier (2006).
A novel norindenoisoquinoline structure reveals a common interfacial inhibitor paradigm for ternary trapping of the topoisomerase I-DNA covalent complex.
  Mol Cancer Ther, 5, 287-295.  
16920739 K.D.Corbett, and J.M.Berger (2006).
Structural basis for topoisomerase VI inhibition by the anti-Hsp90 drug radicicol.
  Nucleic Acids Res, 34, 4269-4277.
PDB code: 2hkj
16549872 K.L.Gilroy, C.Leontiou, K.Padget, J.H.Lakey, and C.A.Austin (2006).
mAMSA resistant human topoisomerase IIbeta mutation G465D has reduced ATP hydrolysis activity.
  Nucleic Acids Res, 34, 1597-1607.  
16598074 M.Duca, D.Guianvarc'h, K.Oussedik, L.Halby, A.Garbesi, D.Dauzonne, C.Monneret, N.Osheroff, C.Giovannangeli, and P.B.Arimondo (2006).
Molecular basis of the targeting of topoisomerase II-mediated DNA cleavage by VP16 derivatives conjugated to triplex-forming oligonucleotides.
  Nucleic Acids Res, 34, 1900-1911.  
15939019 K.D.Corbett, and J.M.Berger (2005).
Structural dissection of ATP turnover in the prototypical GHL ATPase TopoVI.
  Structure, 13, 873-882.
PDB codes: 1z59 1z5a 1z5b 1z5c
15930158 U.H.Manjunatha, A.Maxwell, and V.Nagaraja (2005).
A monoclonal antibody that inhibits mycobacterial DNA gyrase by a novel mechanism.
  Nucleic Acids Res, 33, 3085-3094.  
15749159 Y.Pommier, and J.Cherfils (2005).
Interfacial inhibition of macromolecular interactions: nature's paradigm for drug discovery.
  Trends Pharmacol Sci, 26, 138-145.  
15139806 K.D.Corbett, and J.M.Berger (2004).
Structure, molecular mechanisms, and evolutionary relationships in DNA topoisomerases.
  Annu Rev Biophys Biomol Struct, 33, 95.  
15123801 K.D.Corbett, R.K.Shultzaberger, and J.M.Berger (2004).
The C-terminal domain of DNA gyrase A adopts a DNA-bending beta-pinwheel fold.
  Proc Natl Acad Sci U S A, 101, 7293-7298.
PDB code: 1suu
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.

 

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