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PDBsum entry 2clx
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Contents |
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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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4-arylazo-3,5-diamino-1h-pyrazole cdk inhibitors: sar study, crystal structure in complex with cdk2, selectivity, and cellular effects
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Structure:
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Cell division protein kinase 2. Chain: a. Synonym: p33 protein kinase. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
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Resolution:
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1.80Å
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R-factor:
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0.180
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R-free:
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0.231
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Authors:
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V.Krystof,P.Cankar,I.Frysova,J.Slouka,G.Kontopidis,P.Dzubak, M.Hajduch,W.F.Deazevedo,M.Paprskarova,M.Orsag,J.Rolcik,A.Latr, P.M.Fischer,M.Strnad
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Key ref:
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V.Krystof
et al.
(2006).
4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects.
J Med Chem,
49,
6500-6509.
PubMed id:
DOI:
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Date:
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02-May-06
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Release date:
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01-Nov-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.
293 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]
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+
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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]
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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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DOI no:
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J Med Chem
49:6500-6509
(2006)
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PubMed id:
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4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects.
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V.Krystof,
P.Cankar,
I.Frysová,
J.Slouka,
G.Kontopidis,
P.Dzubák,
M.Hajdúch,
J.Srovnal,
W.F.de Azevedo,
M.Orság,
M.Paprskárová,
J.Rolcík,
A.Látr,
P.M.Fischer,
M.Strnad.
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ABSTRACT
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In a routine screening of our small-molecule compound collection we recently
identified 4-arylazo-3,5-diamino-1H-pyrazoles as a novel group of ATP
antagonists with moderate potency against CDK2-cyclin E. A preliminary SAR study
based on 35 analogues suggests ways in which the pharmacophore could be further
optimized, for example, via substitutions in the 4-aryl ring. Enzyme kinetics
studies with the lead compound and X-ray crystallography of an inhibitor-CDK2
complex demonstrated that its mode of inhibition is competitive. Functional
kinase assays confirmed the selectivity toward CDKs, with a preference for
CDK9-cyclin T1. The most potent inhibitor,
4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol 31b (CAN508), reduced the
frequency of S-phase cells of the cancer cell line HT-29 in antiproliferation
assays. Further observed cellular effects included decreased phosphorylation of
the retinoblastoma protein and the C-terminal domain of RNA polymerase II,
inhibition of mRNA synthesis, and induction of the tumor suppressor protein p53,
all of which are consistent with inhibition of CDK9.
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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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K.Skobridis,
M.Kinigopoulou,
V.Theodorou,
E.Giannousi,
A.Russell,
R.Chauhan,
R.Sala,
N.Brownlow,
S.Kiriakidis,
J.Domin,
A.G.Tzakos,
and
N.J.Dibb
(2010).
Novel imatinib derivatives with altered specificity between Bcr-Abl and FMS, KIT, and PDGF receptors.
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ChemMedChem,
5,
130-139.
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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,
A.Borza,
E.Walzi,
V.Krystof,
M.Maurer,
O.Komina,
and
S.Wandl
(2009).
Outcome of treatment of human HeLa cervical cancer cells with roscovitine strongly depends on the dosage and cell cycle status prior to the treatment.
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J Cell Biochem,
106,
937-955.
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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
