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PDBsum entry 1yrs
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Contents |
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* Residue conservation analysis
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PDB id:
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Cell cycle
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Title:
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Crystal structure of ksp in complex with inhibitor 1
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Structure:
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Kinesin-like protein kif11. Chain: a, b. Fragment: sequence database residues 1-368. Synonym: kinesin-related motor protein eg5, kinesin-like spindle protein hksp, thyroid receptor interacting protein 5, trip5, kinesin- like protein 1. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: kif11, eg5, knsl1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
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Resolution:
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2.50Å
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R-factor:
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0.250
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R-free:
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0.310
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Authors:
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C.D.Cox,M.J.Breslin,B.J.Mariano,P.J.Coleman,C.A.Buser,E.S.Walsh, K.Hamilton,N.E.Kohl,M.Torrent,Y.Yan,L.C.Kuo,G.D.Hartman
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Key ref:
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C.D.Cox
et al.
(2005).
Kinesin spindle protein (KSP) inhibitors. Part 1: The discovery of 3,5-diaryl-4,5-dihydropyrazoles as potent and selective inhibitors of the mitotic kinesin KSP.
Bioorg Med Chem Lett,
15,
2041-2045.
PubMed id:
DOI:
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Date:
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04-Feb-05
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Release date:
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12-Apr-05
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PROCHECK
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Headers
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References
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P52732
(KIF11_HUMAN) -
Kinesin-like protein KIF11 from Homo sapiens
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Seq:
Struc:
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1056 a.a.
330 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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DOI no:
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Bioorg Med Chem Lett
15:2041-2045
(2005)
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PubMed id:
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Kinesin spindle protein (KSP) inhibitors. Part 1: The discovery of 3,5-diaryl-4,5-dihydropyrazoles as potent and selective inhibitors of the mitotic kinesin KSP.
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C.D.Cox,
M.J.Breslin,
B.J.Mariano,
P.J.Coleman,
C.A.Buser,
E.S.Walsh,
K.Hamilton,
H.E.Huber,
N.E.Kohl,
M.Torrent,
Y.Yan,
L.C.Kuo,
G.D.Hartman.
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ABSTRACT
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Optimization of high-throughput screening (HTS) hits resulted in the discovery
of 3,5-diaryl-4,5-dihydropyrazoles as potent and selective inhibitors of KSP.
Dihydropyrazole 15 is a potent, cell-active KSP inhibitor that induces apoptosis
and generates aberrant mitotic spindles in human ovarian carcinoma cells at low
nanomolar concentrations. X-ray crystallographic evidence is presented which
demonstrates that these inhibitors bind in an allosteric pocket of KSP distant
from the nucleotide and microtubule binding sites.
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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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B.Babu,
M.Lee,
L.Lee,
R.Strobel,
O.Brockway,
A.Nickols,
R.Sjoholm,
S.Tzou,
S.Chavda,
D.Desta,
G.Fraley,
A.Siegfried,
W.Pennington,
R.M.Hartley,
C.Westbrook,
S.L.Mooberry,
K.Kiakos,
J.A.Hartley,
and
M.Lee
(2011).
Acetyl analogs of combretastatin A-4: synthesis and biological studies.
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Bioorg Med Chem,
19,
2359-2367.
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C.Bissantz,
B.Kuhn,
and
M.Stahl
(2010).
A medicinal chemist's guide to molecular interactions.
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J Med Chem,
53,
5061-5084.
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H.Prokopcová,
D.Dallinger,
G.Uray,
H.Y.Kaan,
V.Ulaganathan,
F.Kozielski,
C.Laggner,
and
C.O.Kappe
(2010).
Structure-activity relationships and molecular docking of novel dihydropyrimidine-based mitotic Eg5 inhibitors.
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ChemMedChem,
5,
1760-1769.
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K.W.Wood,
L.Lad,
L.Luo,
X.Qian,
S.D.Knight,
N.Nevins,
K.Brejc,
D.Sutton,
A.G.Gilmartin,
P.R.Chua,
R.Desai,
S.P.Schauer,
D.E.McNulty,
R.S.Annan,
L.D.Belmont,
C.Garcia,
Y.Lee,
M.A.Diamond,
L.F.Faucette,
M.Giardiniere,
S.Zhang,
C.M.Sun,
J.D.Vidal,
S.Lichtsteiner,
W.D.Cornwell,
J.D.Greshock,
R.F.Wooster,
J.T.Finer,
R.A.Copeland,
P.S.Huang,
D.J.Morgans,
D.Dhanak,
G.Bergnes,
R.Sakowicz,
and
J.R.Jackson
(2010).
Antitumor activity of an allosteric inhibitor of centromere-associated protein-E.
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Proc Natl Acad Sci U S A,
107,
5839-5844.
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C.Jiang,
Q.You,
F.Liu,
W.Wu,
Q.Guo,
J.Chern,
L.Yang,
and
M.Chen
(2009).
Design, synthesis and evaluation of tetrahydroisoquinolines as new kinesin spindle protein inhibitors.
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Chem Pharm Bull (Tokyo),
57,
567-571.
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D.Huszar,
M.E.Theoclitou,
J.Skolnik,
and
R.Herbst
(2009).
Kinesin motor proteins as targets for cancer therapy.
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Cancer Metastasis Rev,
28,
197-208.
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M.Matsuda,
T.Yamamoto,
A.Matsumura,
and
Y.Kaneda
(2009).
Highly efficient eradication of intracranial glioblastoma using Eg5 siRNA combined with HVJ envelope.
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Gene Ther,
16,
1465-1476.
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L.Amos
(2008).
Spindle assembly: kinesin-5 is in control.
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Curr Biol,
18,
R1146-R1149.
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N.Hayashi,
E.Koller,
L.Fazli,
and
M.E.Gleave
(2008).
Effects of Eg5 knockdown on human prostate cancer xenograft growth and chemosensitivity.
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Prostate,
68,
1283-1295.
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T.C.Krzysiak,
M.Grabe,
and
S.P.Gilbert
(2008).
Getting in Sync with Dimeric Eg5: INITIATION AND REGULATION OF THE PROCESSIVE RUN.
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J Biol Chem,
283,
2078-2087.
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C.Jiang,
Y.Chen,
X.Wang,
and
Q.You
(2007).
Docking studies on kinesin spindle protein inhibitors: an important cooperative 'minor binding pocket' which increases the binding affinity significantly.
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J Mol Model,
13,
987-992.
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I.Garcia-Saez,
S.DeBonis,
R.Lopez,
F.Trucco,
B.Rousseau,
P.Thuéry,
and
F.Kozielski
(2007).
Structure of human Eg5 in complex with a new monastrol-based inhibitor bound in the R configuration.
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J Biol Chem,
282,
9740-9747.
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PDB code:
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J.R.Jackson,
D.R.Patrick,
M.M.Dar,
and
P.S.Huang
(2007).
Targeted anti-mitotic therapies: can we improve on tubulin agents?
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Nat Rev Cancer,
7,
107-117.
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L.Luo,
C.A.Parrish,
N.Nevins,
D.E.McNulty,
A.M.Chaudhari,
J.D.Carson,
V.Sudakin,
A.N.Shaw,
R.Lehr,
H.Zhao,
S.Sweitzer,
L.Lad,
K.W.Wood,
R.Sakowicz,
R.S.Annan,
P.S.Huang,
J.R.Jackson,
D.Dhanak,
R.A.Copeland,
and
K.R.Auger
(2007).
ATP-competitive inhibitors of the mitotic kinesin KSP that function via an allosteric mechanism.
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Nat Chem Biol,
3,
722-726.
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T.Usui
(2007).
Actin- and microtubule-targeting bioprobes: their binding sites and inhibitory mechanisms.
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Biosci Biotechnol Biochem,
71,
300-308.
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B.H.Kwok,
L.C.Kapitein,
J.H.Kim,
E.J.Peterman,
C.F.Schmidt,
and
T.M.Kapoor
(2006).
Allosteric inhibition of kinesin-5 modulates its processive directional motility.
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Nat Chem Biol,
2,
480-485.
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D.A.Davis,
S.H.Sarkar,
M.Hussain,
Y.Li,
and
F.H.Sarkar
(2006).
Increased therapeutic potential of an experimental anti-mitotic inhibitor SB715992 by genistein in PC-3 human prostate cancer cell line.
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BMC Cancer,
6,
22.
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D.A.Skoufias,
S.DeBonis,
Y.Saoudi,
L.Lebeau,
I.Crevel,
R.Cross,
R.H.Wade,
D.Hackney,
and
F.Kozielski
(2006).
S-trityl-L-cysteine is a reversible, tight binding inhibitor of the human kinesin Eg5 that specifically blocks mitotic progression.
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J Biol Chem,
281,
17559-17569.
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J.C.Cochran,
T.C.Krzysiak,
and
S.P.Gilbert
(2006).
Pathway of ATP hydrolysis by monomeric kinesin Eg5.
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Biochemistry,
45,
12334-12344.
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M.R.Miglarese,
and
R.O.Carlson
(2006).
Development of new cancer therapeutic agents targeting mitosis.
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Expert Opin Investig Drugs,
15,
1411-1425.
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S.Brier,
D.Lemaire,
S.DeBonis,
F.Kozielski,
and
E.Forest
(2006).
Use of hydrogen/deuterium exchange mass spectrometry and mutagenesis as a tool to identify the binding region of inhibitors targeting the human mitotic kinesin Eg5.
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Rapid Commun Mass Spectrom,
20,
456-462.
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V.Sarli,
and
A.Giannis
(2006).
Inhibitors of mitotic kinesins: next-generation antimitotics.
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ChemMedChem,
1,
293-298.
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Z.Maliga,
J.Xing,
H.Cheung,
L.J.Juszczak,
J.M.Friedman,
and
S.S.Rosenfeld
(2006).
A pathway of structural changes produced by monastrol binding to Eg5.
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J Biol Chem,
281,
7977-7982.
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Z.Maliga,
and
T.J.Mitchison
(2006).
Small-molecule and mutational analysis of allosteric Eg5 inhibition by monastrol.
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BMC Chem Biol,
6,
2.
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J.C.Cochran,
and
S.P.Gilbert
(2005).
ATPase mechanism of Eg5 in the absence of microtubules: insight into microtubule activation and allosteric inhibition by monastrol.
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Biochemistry,
44,
16633-16648.
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V.Sarli,
S.Huemmer,
N.Sunder-Plassmann,
T.U.Mayer,
and
A.Giannis
(2005).
Synthesis and biological evaluation of novel EG5 inhibitors.
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Chembiochem,
6,
2005-2013.
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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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Links
