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PDBsum entry 2a0c
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* Residue conservation analysis
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PDB id:
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Transferase
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Title:
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Human cdk2 in complex with olomoucine ii, a novel 2,6,9-trisubstituted purine cyclin-dependent kinase inhibitor
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Structure:
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Cell division protein kinase 2. Chain: x. Synonym: cyclin dependant kinase 2, cdk2, p33 protein kinase. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: cdk2.
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Resolution:
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1.95Å
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R-factor:
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0.194
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R-free:
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0.244
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Authors:
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V.Krystof,I.W.Mcnae,M.D.Walkinshaw,P.M.Fischer,P.Muller,B.Vojtesek, M.Orsag,L.Havlicek,M.Strnad
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Key ref:
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V.Krystof
et al.
(2005).
Antiproliferative activity of olomoucine II, a novel 2,6,9-trisubstituted purine cyclin-dependent kinase inhibitor.
Cell Mol Life Sci,
62,
1763-1771.
PubMed id:
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Date:
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16-Jun-05
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Release date:
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24-Jan-06
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PROCHECK
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Headers
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References
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P24941
(CDK2_HUMAN) -
Cyclin-dependent kinase 2 from Homo sapiens
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Seq:
Struc:
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298 a.a.
294 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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Enzyme class:
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E.C.2.7.11.22
- cyclin-dependent kinase.
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Reaction:
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1.
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L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
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2.
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L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
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L-seryl-[protein]
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+
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ATP
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=
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O-phospho-L-seryl-[protein]
Bound ligand (Het Group name = )
matches with 42.11% similarity
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ADP
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+
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H(+)
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L-threonyl-[protein]
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+
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ATP
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=
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O-phospho-L-threonyl-[protein]
Bound ligand (Het Group name = )
matches with 42.11% similarity
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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Cell Mol Life Sci
62:1763-1771
(2005)
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PubMed id:
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Antiproliferative activity of olomoucine II, a novel 2,6,9-trisubstituted purine cyclin-dependent kinase inhibitor.
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V.Krystof,
I.W.McNae,
M.D.Walkinshaw,
P.M.Fischer,
P.Müller,
B.Vojtesek,
M.Orság,
L.Havlícek,
M.Strnad.
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ABSTRACT
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The study describes the protein kinase selectivity profile, as well as the
binding mode of olomoucine II in the catalytic cleft of CDK2, as determined from
cocrystal analysis. Apart from the main cell cycle-regulating kinase CDK2,
olomoucine II exerts specificity for CDK7 and CDK9, with important functions in
the regulation of RNA transcription. In vitro anticancer activity of the
inhibitor in a panel of tumor cell lines shows a wide potency range with a
slight preference for cells harboring a wild-type p53 gene. Cell-based assays
confirmed activation of p53 protein levels and events leading to accumulation of
p21(WAF1). Additionally, in olomoucine II-treated cells, Mdm2 was found to form
a complex with the ribosomal protein L11, which inhibits Mdm2 ubiquitin ligase
function. We conclude that perturbations in RNA synthesis may lead to activation
of p53 and that this contributes to the antiproliferative potency of
cyclindependent kinase inhibitors.
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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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C.Fang,
Z.Xiao,
and
Z.Guo
(2011).
Generation and validation of the first predictive pharmacophore model for cyclin-dependent kinase 9 inhibitors.
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J Mol Graph Model,
29,
800-808.
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Z.Holubcová,
P.Matula,
M.Sedláčková,
V.Vinarský,
D.Doležalová,
T.Bárta,
P.Dvořák,
and
A.Hampl
(2011).
Human embryonic stem cells suffer from centrosomal amplification.
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Stem Cells,
29,
46-56.
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J.Holcakova,
P.Tomasec,
J.J.Bugert,
E.C.Wang,
G.W.Wilkinson,
R.Hrstka,
V.Krystof,
M.Strnad,
and
B.Vojtesek
(2010).
The inhibitor of cyclin-dependent kinases, olomoucine II, exhibits potent antiviral properties.
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Antivir Chem Chemother,
20,
133-142.
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Z.Koledova,
L.R.Kafkova,
L.Calabkova,
V.Krystof,
P.Dolezel,
and
V.Divoky
(2010).
Cdk2 inhibition prolongs G1 phase progression in mouse embryonic stem cells.
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Stem Cells Dev,
19,
181-194.
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J.Wesierska-Gadek,
and
V.Krystof
(2009).
Selective cyclin-dependent kinase inhibitors discriminating between cell cycle and transcriptional kinases: future reality or utopia?
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Ann N Y Acad Sci,
1171,
228-241.
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M.Paprskárová,
V.Krystof,
R.Jorda,
P.Dzubák,
M.Hajdúch,
J.Wesierska-Gadek,
and
M.Strnad
(2009).
Functional p53 in cells contributes to the anticancer effect of the cyclin-dependent kinase inhibitor roscovitine.
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J Cell Biochem,
107,
428-437.
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M.Rouchal,
M.Nečas,
F.P.de Carvalho,
and
R.Vícha
(2009).
2-(1-Adamant-yl)-1-{4-[(2-chloro-9-isopropyl-9H-purin-6-yl)amino-meth-yl]phen-yl}ethanone.
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Acta Crystallogr Sect E Struct Rep Online,
65,
o298-o299.
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T.N.Feinstein,
and
A.D.Linstedt
(2007).
Mitogen-activated protein kinase kinase 1-dependent Golgi unlinking occurs in G2 phase and promotes the G2/M cell cycle transition.
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Mol Biol Cell,
18,
594-604.
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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.
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Links
