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* Residue conservation analysis
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Gene Ontology (GO) functional annotation
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Cellular component
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chromosome
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1 term
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Biological process
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DNA topological change
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1 term
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Biochemical function
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DNA binding
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3 terms
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DOI no:
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Antimicrob Agents Chemother
48:1856-1864
(2004)
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PubMed id:
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Crystal structures of Escherichia coli topoisomerase IV ParE subunit (24 and 43 kilodaltons): a single residue dictates differences in novobiocin potency against topoisomerase IV and DNA gyrase.
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S.Bellon,
J.D.Parsons,
Y.Wei,
K.Hayakawa,
L.L.Swenson,
P.S.Charifson,
J.A.Lippke,
R.Aldape,
C.H.Gross.
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ABSTRACT
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Topoisomerase IV and DNA gyrase are related bacterial type II topoisomerases
that utilize the free energy from ATP hydrolysis to catalyze topological changes
in the bacterial genome. The essential function of DNA gyrase is the
introduction of negative DNA supercoils into the genome, whereas the essential
function of topoisomerase IV is to decatenate daughter chromosomes following
replication. Here, we report the crystal structures of a 43-kDa N-terminal
fragment of Escherichia coli topoisomerase IV ParE subunit complexed with
adenylyl-imidodiphosphate at 2.0-A resolution and a 24-kDa N-terminal fragment
of the ParE subunit complexed with novobiocin at 2.1-A resolution. The solved
ParE structures are strikingly similar to the known gyrase B (GyrB) subunit
structures. We also identified single-position equivalent amino acid residues in
ParE (M74) and in GyrB (I78) that, when exchanged, increased the potency of
novobiocin against topoisomerase IV by nearly 20-fold (to 12 nM). The
corresponding exchange in gyrase (I78 M) yielded a 20-fold decrease in the
potency of novobiocin (to 1.0 micro M). These data offer an explanation for the
observation that novobiocin is significantly less potent against topoisomerase
IV than against DNA gyrase. Additionally, the enzyme kinetic parameters were
affected. In gyrase, the ATP K(m) increased approximately 5-fold and the V(max)
decreased approximately 30%. In contrast, the topoisomerase IV ATP K(m)
decreased by a factor of 6, and the V(max) increased approximately 2-fold from
the wild-type values. These data demonstrate that the ParE M74 and GyrB I78 side
chains impart opposite effects on the enzyme's substrate affinity and catalytic
efficiency.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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F.P.Davis
(2011).
Proteome-wide prediction of overlapping small molecule and protein binding sites using structure.
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Mol Biosyst, 7,
545-557.
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C.Sissi,
and
M.Palumbo
(2010).
In front of and behind the replication fork: bacterial type IIA topoisomerases.
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Cell Mol Life Sci, 67,
2001-2024.
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O.Doppelt-Azeroual,
F.Moriaud,
F.Delfaud,
and
A.G.de Brevern
(2009).
Analysis of HSP90-related folds with MED-SuMo classification approach.
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Drug Des Devel Ther, 3,
59-72.
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P.Forterre,
and
D.Gadelle
(2009).
Phylogenomics of DNA topoisomerases: their origin and putative roles in the emergence of modern organisms.
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Nucleic Acids Res, 37,
679-692.
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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.
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Antimicrob Agents Chemother, 53,
3822-3831.
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A.J.Schoeffler,
and
J.M.Berger
(2008).
DNA topoisomerases: harnessing and constraining energy to govern chromosome topology.
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Q Rev Biophys, 41,
41.
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L.A.Plesniak,
K.Botsch,
M.Leibrand,
M.Kelly,
D.Sem,
J.A.Adams,
and
P.Jennings
(2008).
Transferred NOE and saturation transfer difference NMR studies of novobiocin binding to EnvZ suggest binding mode similar to DNA gyrase.
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Chem Biol Drug Des, 71,
28-35.
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N.D.Thomsen,
and
J.M.Berger
(2008).
Structural frameworks for considering microbial protein- and nucleic acid-dependent motor ATPases.
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Mol Microbiol, 69,
1071-1090.
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D.A.Ostrov,
J.A.Hernández Prada,
P.E.Corsino,
K.A.Finton,
N.Le,
and
T.C.Rowe
(2007).
Discovery of novel DNA gyrase inhibitors by high-throughput virtual screening.
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Antimicrob Agents Chemother, 51,
3688-3698.
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I.Laponogov,
D.A.Veselkov,
M.K.Sohi,
X.S.Pan,
A.Achari,
C.Yang,
J.D.Ferrara,
L.M.Fisher,
and
M.R.Sanderson
(2007).
Breakage-reunion domain of Streptococcus pneumoniae topoisomerase IV: crystal structure of a gram-positive quinolone target.
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PLoS ONE, 2,
e301.
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PDB code:
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L.L.Silver
(2007).
Multi-targeting by monotherapeutic antibacterials.
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Nat Rev Drug Discov, 6,
41-55.
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T.H.Grossman,
D.J.Bartels,
S.Mullin,
C.H.Gross,
J.D.Parsons,
Y.Liao,
A.L.Grillot,
D.Stamos,
E.R.Olson,
P.S.Charifson,
and
N.Mani
(2007).
Dual targeting of GyrB and ParE by a novel aminobenzimidazole class of antibacterial compounds.
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Antimicrob Agents Chemother, 51,
657-666.
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J.J.Barker
(2006).
Antibacterial drug discovery and structure-based design.
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Drug Discov Today, 11,
391-404.
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N.Mani,
C.H.Gross,
J.D.Parsons,
B.Hanzelka,
U.Müh,
S.Mullin,
Y.Liao,
A.L.Grillot,
D.Stamos,
P.S.Charifson,
and
T.H.Grossman
(2006).
In vitro characterization of the antibacterial spectrum of novel bacterial type II topoisomerase inhibitors of the aminobenzimidazole class.
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Antimicrob Agents Chemother, 50,
1228-1237.
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K.D.Corbett,
and
J.M.Berger
(2005).
Structural dissection of ATP turnover in the prototypical GHL ATPase TopoVI.
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Structure, 13,
873-882.
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PDB codes:
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K.Yamashiro,
and
A.Yamagishi
(2005).
Characterization of the DNA gyrase from the thermoacidophilic archaeon Thermoplasma acidophilum.
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J Bacteriol, 187,
8531-8536.
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M.B.Schmid
(2004).
Seeing is believing: the impact of structural genomics on antimicrobial drug discovery.
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Nat Rev Microbiol, 2,
739-746.
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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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