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protein dna_rna metals links
Isomerase/DNA PDB id
2rgr
Jmol
Contents
Protein chain
721 a.a. *
DNA/RNA
Metals
_MG
Waters ×48
* Residue conservation analysis
PDB id:
2rgr
Name: Isomerase/DNA
Title: Topoisomerase iia bound to g-segment DNA
Structure: DNA topoisomerase 2. Chain: a. Fragment: DNA binding and cleavage domain (residues 419- 1177). Synonym: DNA topoisomerase ii. Engineered: yes. DNA. Chain: c. Engineered: yes.
Source: Saccharomyces cerevisiae. Baker's yeast. Organism_taxid: 4932. Gene: top2, tor3. Expressed in: saccharomyces cerevisiae. Expression_system_taxid: 4932. Synthetic: yes. Synthetic: yes
Resolution:
3.00Å     R-factor:   0.231     R-free:   0.278
Authors: K.C.Dong,J.M.Berger
Key ref:
K.C.Dong and J.M.Berger (2007). Structural basis for gate-DNA recognition and bending by type IIA topoisomerases. Nature, 450, 1201-1205. PubMed id: 18097402 DOI: 10.1038/nature06396
Date:
04-Oct-07     Release date:   25-Dec-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P06786  (TOP2_YEAST) -  DNA topoisomerase 2
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1428 a.a.
721 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.5.99.1.3  - Dna topoisomerase (ATP-hydrolyzing).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP-dependent breakage, passage and rejoining of double-stranded DNA.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     chromosome   1 term 
  Biological process     DNA metabolic process   3 terms 
  Biochemical function     DNA binding     4 terms  

 

 
DOI no: 10.1038/nature06396 Nature 450:1201-1205 (2007)
PubMed id: 18097402  
 
 
Structural basis for gate-DNA recognition and bending by type IIA topoisomerases.
K.C.Dong, J.M.Berger.
 
  ABSTRACT  
 
Type II topoisomerases disentangle DNA to facilitate chromosome segregation, and represent a major class of therapeutic targets. Although these enzymes have been studied extensively, a molecular understanding of DNA binding has been lacking. Here we present the structure of a complex between the DNA-binding and cleavage core of Saccharomyces cerevisiae Topo II (also known as Top2) and a gate-DNA segment. The structure reveals that the enzyme enforces a 150 degrees DNA bend through a mechanism similar to that of remodelling proteins such as integration host factor. Large protein conformational changes accompany DNA deformation, creating a bipartite catalytic site that positions the DNA backbone near a reactive tyrosine and a coordinated magnesium ion. This configuration closely resembles the catalytic site of type IA topoisomerases, reinforcing an evolutionary link between these structurally and functionally distinct enzymes. Binding of DNA facilitates opening of an enzyme dimerization interface, providing visual evidence for a key step in DNA transport.
 
  Selected figure(s)  
 
Figure 2.
Figure 2: Topo II severely bends DNA. a, Comparison of DNA bending caused by Topo II (left) and IHF^28 (right; Protein Data Bank (PDB) accession number, 1IHF). DNA-binding -hairpins and intercalating aliphatic amino acids are highlighted in green and are shown in the inset. For Topo II, the WHDs and catalytic tyrosines are shown as magenta/grey ribbons and red spheres, respectively; the body of IHF is shown as a grey ribbon. b, DNA (orange) and tower domain (purple) interactions. Residues that contact DNA are shown as sticks. c, DNA-bending induced by Ile 833 (green spheres). Electron density from a simulated annealed omit map is shown contoured around the duplex at 1 . 		Figure 4.
Figure 4: Close up of the Topo II active site. The TOPRIM fold and WHD of one protomer are coloured cyan and pink, respectively, whereas the WHD of the partner subunit is coloured magenta. Key residues are shown as sticks and are labelled. A green sphere marks the midpoint of the nick between the +1 and -1 position of double-stranded DNA, and corresponds to the approximate position of the scissile phosphodiester linkage.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2007, 450, 1201-1205) copyright 2007.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21321228 G.Witz, G.Dietler, and A.Stasiak (2011).
Tightening of DNA knots by supercoiling facilitates their unknotting by type II DNA topoisomerases.
  Proc Natl Acad Sci U S A, 108, 3608-3611.  
21358820 K.L.Gilroy, and C.A.Austin (2011).
The Impact of the C-Terminal Domain on the Interaction of Human DNA Topoisomerase II α and β with DNA.
  PLoS One, 6, e14693.  
21419530 K.Y.Jun, E.Y.Lee, M.J.Jung, O.H.Lee, E.S.Lee, H.Y.Park Choo, Y.Na, and Y.Kwon (2011).
Synthesis, biological evaluation, and molecular docking study of 3-(3'-heteroatom substituted-2'-hydroxy-1'-propyloxy) xanthone analogues as novel topoisomerase IIα catalytic inhibitor.
  Eur J Med Chem, 46, 1964-1971.  
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.  
20854710 W.Yang (2011).
Nucleases: diversity of structure, function and mechanism.
  Q Rev Biophys, 44, 1.  
21482796 Z.Zhang, B.Cheng, and Y.C.Tse-Dinh (2011).
Crystal structure of a covalent intermediate in DNA cleavage and rejoining by Escherichia coli DNA topoisomerase I.
  Proc Natl Acad Sci U S A, 108, 6939-6944.  
20675723 A.J.Schoeffler, A.P.May, and J.M.Berger (2010).
A domain insertion in Escherichia coli GyrB adopts a novel fold that plays a critical role in gyrase function.
  Nucleic Acids Res, 38, 7830-7844.
PDB code: 3nuh
20802486 A.Wohlkonig, P.F.Chan, A.P.Fosberry, P.Homes, J.Huang, M.Kranz, V.R.Leydon, T.J.Miles, N.D.Pearson, R.L.Perera, A.J.Shillings, M.N.Gwynn, and B.D.Bax (2010).
Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance.
  Nat Struct Mol Biol, 17, 1152-1153.
PDB codes: 2xkj 2xkk
20686482 B.D.Bax, P.F.Chan, D.S.Eggleston, A.Fosberry, D.R.Gentry, F.Gorrec, I.Giordano, M.M.Hann, A.Hennessy, M.Hibbs, J.Huang, E.Jones, J.Jones, K.K.Brown, C.J.Lewis, E.W.May, M.R.Saunders, O.Singh, C.E.Spitzfaden, C.Shen, A.Shillings, A.J.Theobald, A.Wohlkonig, N.D.Pearson, and M.N.Gwynn (2010).
Type IIA topoisomerase inhibition by a new class of antibacterial agents.
  Nature, 466, 935-940.
PDB codes: 2xco 2xcq 2xcr 2xcs 2xct
20485342 B.H.Schmidt, A.B.Burgin, J.E.Deweese, N.Osheroff, and J.M.Berger (2010).
A novel and unified two-metal mechanism for DNA cleavage by type II and IA topoisomerases.
  Nature, 465, 641-644.
PDB codes: 3l4j 3l4k
20165898 C.Sissi, and M.Palumbo (2010).
In front of and behind the replication fork: bacterial type IIA topoisomerases.
  Cell Mol Life Sci, 67, 2001-2024.  
20192771 D.Meluzzi, D.E.Smith, and G.Arya (2010).
Biophysics of knotting.
  Annu Rev Biophys, 39, 349-366.  
20006518 G.L.Chee, J.C.Yalowich, A.Bodner, X.Wu, and B.B.Hasinoff (2010).
A diazirine-based photoaffinity etoposide probe for labeling topoisomerase II.
  Bioorg Med Chem, 18, 830-838.  
20026582 G.Witz, and A.Stasiak (2010).
DNA supercoiling and its role in DNA decatenation and unknotting.
  Nucleic Acids Res, 38, 2119-2133.  
21079245 H.Ryu, M.Furuta, D.Kirkpatrick, S.P.Gygi, and Y.Azuma (2010).
PIASy-dependent SUMOylation regulates DNA topoisomerase IIalpha activity.
  J Cell Biol, 191, 783-794.  
20596531 I.Laponogov, X.S.Pan, D.A.Veselkov, K.E.McAuley, L.M.Fisher, and M.R.Sanderson (2010).
Structural basis of gate-DNA breakage and resealing by type II topoisomerases.
  PLoS One, 5, e11338.
PDB codes: 3k9f 3ksa 3ksb 3ltn
  20703329 J.E.Deweese, and N.Osheroff (2010).
The use of divalent metal ions by type II topoisomerases.
  Metallomics, 2, 450-459.  
20805881 J.Piton, S.Petrella, M.Delarue, G.André-Leroux, V.Jarlier, A.Aubry, and C.Mayer (2010).
Structural insights into the quinolone resistance mechanism of Mycobacterium tuberculosis DNA gyrase.
  PLoS One, 5, e12245.
PDB codes: 3ifz 3ig0 3m4i
19773249 M.Li, Z.H.Miao, Z.Chen, Q.Chen, M.Gui, L.P.Lin, P.Sun, Y.H.Yi, and J.Ding (2010).
Echinoside A, a new marine-derived anticancer saponin, targets topoisomerase2alpha by unique interference with its DNA binding and catalytic cycle.
  Ann Oncol, 21, 597-607.  
20127325 P.Xie (2010).
Dynamics of strand passage catalyzed by topoisomerase II.
  Eur Biophys J, 39, 1251-1259.  
20419121 R.E.Hawtin, D.E.Stockett, J.A.Byl, R.S.McDowell, T.Nguyen, M.R.Arkin, A.Conroy, W.Yang, N.Osheroff, and J.A.Fox (2010).
Voreloxin is an anticancer quinolone derivative that intercalates DNA and poisons topoisomerase II.
  PLoS One, 5, e10186.  
21087076 W.Yang (2010).
Topoisomerases and site-specific recombinases: similarities in structure and mechanism.
  Crit Rev Biochem Mol Biol, 45, 520-534.  
20174470 Y.Timsit, and P.Várnai (2010).
Helical chirality: a link between local interactions and global topology in DNA.
  PLoS One, 5, e9326.  
20365765 Z.Liu, L.Zechiedrich, and H.S.Chan (2010).
Local site preference rationalizes disentangling by DNA topoisomerases.
  Phys Rev E Stat Nonlin Soft Matter Phys, 81, 031902.  
20075860 Z.M.Petrushenko, Y.Cui, W.She, and V.V.Rybenkov (2010).
Mechanics of DNA bridging by bacterial condensin MukBEF in vitro and in singulo.
  EMBO J, 29, 1126-1135.  
19700639 A.Dar, D.Prusty, N.Mondal, and S.K.Dhar (2009).
A unique 45-amino-acid region in the toprim domain of Plasmodium falciparum gyrase B is essential for its activity.
  Eukaryot Cell, 8, 1759-1769.  
19666507 A.Gubaev, M.Hilbert, and D.Klostermeier (2009).
The DNA-gate of Bacillus subtilis gyrase is predominantly in the closed conformation during the DNA supercoiling reaction.
  Proc Natl Acad Sci U S A, 106, 13278-13283.  
19383879 A.Vologodskii (2009).
Theoretical models of DNA topology simplification by type IIA DNA topoisomerases.
  Nucleic Acids Res, 37, 3125-3133.  
20145800 A.Vologodskii, and V.V.Rybenkov (2009).
Simulation of DNA catenanes.
  Phys Chem Chem Phys, 11, 10543-10552.  
19188255 C.Sissi, and M.Palumbo (2009).
Effects of magnesium and related divalent metal ions in topoisomerase structure and function.
  Nucleic Acids Res, 37, 702-711.  
19342777 G.Fu, J.Wu, D.Zhu, Y.Hu, L.Bi, X.E.Zhang, and d.a. .C.Wang (2009).
Crystallization and preliminary crystallographic studies of Mycobacterium tuberculosis DNA gyrase B C-terminal domain, part of the enzyme reaction core.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 65, 350-352.  
19596812 G.Fu, J.Wu, W.Liu, D.Zhu, Y.Hu, J.Deng, X.E.Zhang, L.Bi, and D.C.Wang (2009).
Crystal structure of DNA gyrase B' domain sheds lights on the mechanism for T-segment navigation.
  Nucleic Acids Res, 37, 5908-5916.
PDB code: 2zjt
19530238 H.Le, S.Singh, S.J.Shih, N.Du, S.Schnyder, G.A.Loredo, C.Bien, L.Michaelis, A.Toor, M.O.Diaz, and A.T.Vaughan (2009).
Rearrangements of the MLL gene are influenced by DNA secondary structure, potentially mediated by topoisomerase II binding.
  Genes Chromosomes Cancer, 48, 806-815.  
19448616 I.Laponogov, M.K.Sohi, D.A.Veselkov, X.S.Pan, R.Sawhney, A.W.Thompson, K.E.McAuley, L.M.Fisher, and M.R.Sanderson (2009).
Structural insight into the quinolone-DNA cleavage complex of type IIA topoisomerases.
  Nat Struct Mol Biol, 16, 667-669.
PDB codes: 3foe 3fof
19222228 J.E.Deweese, A.M.Burch, A.B.Burgin, and N.Osheroff (2009).
Use of divalent metal ions in the dna cleavage reaction of human type II topoisomerases.
  Biochemistry, 48, 1862-1869.  
19697956 J.E.Deweese, F.P.Guengerich, A.B.Burgin, and N.Osheroff (2009).
Metal ion interactions in the DNA cleavage/ligation active site of human topoisomerase IIalpha.
  Biochemistry, 48, 8940-8947.  
19042970 J.E.Deweese, and N.Osheroff (2009).
The DNA cleavage reaction of topoisomerase II: wolf in sheep's clothing.
  Nucleic Acids Res, 37, 738-748.  
19166355 J.E.Deweese, and N.Osheroff (2009).
Coordinating the two protomer active sites of human topoisomerase IIalpha: nicks as topoisomerase II poisons.
  Biochemistry, 48, 1439-1441.  
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.  
19491928 M.Yanagida (2009).
Clearing the way for mitosis: is cohesin a target?
  Nat Rev Mol Cell Biol, 10, 489-496.  
19647513 N.De Jonge, A.Garcia-Pino, L.Buts, S.Haesaerts, D.Charlier, K.Zangger, L.Wyns, H.De Greve, and R.Loris (2009).
Rejuvenation of CcdB-poisoned gyrase by an intrinsically disordered protein domain.
  Mol Cell, 35, 154-163.
PDB codes: 3g7z 3hpw
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.  
19564360 X.S.Pan, K.A.Gould, and L.M.Fisher (2009).
Probing the differential interactions of quinazolinedione PD 0305970 and quinolones with gyrase and topoisomerase IV.
  Antimicrob Agents Chemother, 53, 3822-3831.  
19240147 Z.Liu, R.W.Deibler, H.S.Chan, and L.Zechiedrich (2009).
The why and how of DNA unlinking.
  Nucleic Acids Res, 37, 661-671.  
18755053 A.J.Schoeffler, and J.M.Berger (2008).
DNA topoisomerases: harnessing and constraining energy to govern chromosome topology.
  Q Rev Biophys, 41, 41.  
18824478 A.T.Jonstrup, T.Thomsen, Y.Wang, B.R.Knudsen, J.Koch, and A.H.Andersen (2008).
Hairpin structures formed by alpha satellite DNA of human centromeres are cleaved by human topoisomerase IIalpha.
  Nucleic Acids Res, 36, 6165-6174.  
18723844 A.T.Rogojina, and J.L.Nitiss (2008).
Isolation and characterization of mAMSA-hypersensitive mutants. Cytotoxicity of Top2 covalent complexes containing DNA single strand breaks.
  J Biol Chem, 283, 29239-29250.  
18635352 C.D'Ambrosio, G.Kelly, K.Shirahige, and F.Uhlmann (2008).
Condensin-dependent rDNA decatenation introduces a temporal pattern to chromosome segregation.
  Curr Biol, 18, 1084-1089.  
18202637 D.J.Stevenson (2008).
A planetary perspective on the deep Earth.
  Nature, 451, 261-265.  
18596031 E.Toyoda, S.Kagaya, I.G.Cowell, A.Kurosawa, K.Kamoshita, K.Nishikawa, S.Iiizumi, H.Koyama, C.A.Austin, and N.Adachi (2008).
NK314, a Topoisomerase II Inhibitor That Specifically Targets the {alpha} Isoform.
  J Biol Chem, 283, 23711-23720.  
18653531 J.E.Deweese, A.B.Burgin, and N.Osheroff (2008).
Human topoisomerase IIalpha uses a two-metal-ion mechanism for DNA cleavage.
  Nucleic Acids Res, 36, 4883-4893.  
18723572 X.S.Pan, M.Dias, M.Palumbo, and L.M.Fisher (2008).
Clerocidin selectively modifies the gyrase-DNA gate to induce irreversible and reversible DNA damage.
  Nucleic Acids Res, 36, 5516-5529.  
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.