PDBsum entry 2clx

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Transferase PDB id
Protein chain
293 a.a. *
Waters ×253
* Residue conservation analysis
PDB id:
Name: Transferase
Title: 4-arylazo-3,5-diamino-1h-pyrazole cdk inhibitors: sar study, crystal structure in complex with cdk2, selectivity, and cellular effects
Structure: Cell division protein kinase 2. Chain: a. Synonym: p33 protein kinase. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
1.80Å     R-factor:   0.180     R-free:   0.231
Authors: 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
Key ref: 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: 17064068 DOI: 10.1021/jm0605740
02-May-06     Release date:   01-Nov-06    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2
298 a.a.
293 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Cyclin-dependent kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
+ protein
+ phosphoprotein
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cyclin-dependent protein kinase holoenzyme complex   15 terms 
  Biological process     regulation of gene silencing   27 terms 
  Biochemical function     nucleotide binding     12 terms  


DOI no: 10.1021/jm0605740 J Med Chem 49:6500-6509 (2006)
PubMed id: 17064068  
4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects.
V.Krystof, P.Cankar, I.Frysová, J.Slouka, G.Kontopidis, P.Dzubák, M.Hajdúch, J.Srovnal, Azevedo, M.Orság, M.Paprskárová, J.Rolcík, A.Látr, P.M.Fischer, M.Strnad.
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.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21333571 C.Fang, Z.Xiao, and Z.Guo (2011).
Generation and validation of the first predictive pharmacophore model for cyclin-dependent kinase 9 inhibitors.
  J Mol Graph Model, 29, 800-808.  
19950162 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.
  ChemMedChem, 5, 130-139.  
19737069 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.
  Stem Cells Dev, 19, 181-194.  
19180585 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.
  J Cell Biochem, 106, 937-955.  
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