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PDBsum entry 2b54

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protein ligands links
Transferase PDB id
2b54
Jmol PyMol
Contents
Protein chain
298 a.a. *
Ligands
D05
Waters ×318
* Residue conservation analysis
PDB id:
2b54
Name: Transferase
Title: Human cyclin dependent kinase 2 (ckd2)complexed with din- 232305
Structure: Cell division protein kinase 2. Chain: a. Synonym: p33 protein kinase, cdk2. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
Resolution:
1.85Å     R-factor:   0.158     R-free:   0.263
Authors: C.-C.Chang
Key ref: J.A.Markwalder et al. (2004). Synthesis and biological evaluation of 1-aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one inhibitors of cyclin-dependent kinases. J Med Chem, 47, 5894-5911. PubMed id: 15537345 DOI: 10.1021/jm020455u
Date:
27-Sep-05     Release date:   11-Oct-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

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

 Enzyme reactions 
   Enzyme class: E.C.2.7.11.22  - Cyclin-dependent kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
= ADP
+ phosphoprotein
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cyclin A1-CDK2 complex   19 terms 
  Biological process     regulation of gene silencing   32 terms 
  Biochemical function     nucleotide binding     13 terms  

 

 
    reference    
 
 
DOI no: 10.1021/jm020455u J Med Chem 47:5894-5911 (2004)
PubMed id: 15537345  
 
 
Synthesis and biological evaluation of 1-aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one inhibitors of cyclin-dependent kinases.
J.A.Markwalder, M.R.Arnone, P.A.Benfield, M.Boisclair, C.R.Burton, C.H.Chang, S.S.Cox, P.M.Czerniak, C.L.Dean, D.Doleniak, R.Grafstrom, B.A.Harrison, R.F.Kaltenbach, D.A.Nugiel, K.A.Rossi, S.R.Sherk, L.M.Sisk, P.Stouten, G.L.Trainor, P.Worland, S.P.Seitz.
 
  ABSTRACT  
 
Using a high-throughput screening strategy, a series of 1-aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-ones was identified that inhibit the cyclin-dependent kinase (CDK) 4/cyclin D1 complex-mediated phosphorylation of a protein substrate with IC(50)s in the low micromolar range. On the basis of preliminary structure-activity relationships (SAR), a model was proposed in which these inhibitors occupy the ATP-binding site of the enzyme, forming critical hydrogen bonds to the same residue (Val96) to which the amino group in ATP is presumed to bind. X-ray diffraction studies on a later derivative bound to CDK2 support this binding mode. Iterative cycles of synthesis and screening lead to a novel series of potent, CDK2-selective 6-(arylmethyl)pyrazolopyrimidinones. Placement of a hydrogen-bond donor in the meta-position on the 6-arylmethyl group resulted in approximately 100-fold increases in CDK4 affinity, giving ligands that were equipotent inhibitors of CDK4 and CDK2. These compounds exhibit antiproliferative effects in the NCI HCT116 and other cell lines. The potency of these antiproliferative effects is enhanced in anilide derivatives and translates into tumor growth inhibition in a mouse xenograft model.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
22606090 J.Liu, Z.Q.Cai, Y.Wang, C.Y.Li, and L.F.Xu (2012).
1-(2,4-Dichloro-phen-yl)-5-(2-nitro-anilino)-1H-pyrazole-4-carbonitrile.
  Acta Crystallogr Sect E Struct Rep Online, 68, o1142.  
21384418 H.A.Abd El Razik, and A.E.Abdel Wahab (2011).
Synthesis and biological evaluation of some novel fused pyrazolopyrimidines as potential anticancer and antimicrobial agents.
  Arch Pharm (Weinheim), 344, 184-196.  
18591806 X.Zhai, Y.F.Zhao, Y.J.Liu, Y.Zhang, F.Q.Xun, J.Liu, and P.Gong (2008).
Synthesis and cytotoxicity studies of novel [1,2,4]triazolo[1,5-a]pyrimidine-7-amines.
  Chem Pharm Bull (Tokyo), 56, 941-945.  
17700841 C.J.Smith, F.J.Iglesias-Sigüenza, I.R.Baxendale, and S.V.Ley (2007).
Flow and batch mode focused microwave synthesis of 5-amino-4-cyanopyrazoles and their further conversion to 4-aminopyrazolopyrimidines.
  Org Biomol Chem, 5, 2758-2761.  
16935750 S.T.Weiss, N.R.McIntyre, M.L.McLaughlin, and D.J.Merkler (2006).
The development of molecular clamps as drugs.
  Drug Discov Today, 11, 819-824.  
16075305 K.A.Rossi, J.A.Markwalder, S.P.Seitz, C.H.Chang, S.Cox, M.D.Boisclair, L.Brizuela, S.L.Brenner, and P.F.Stouten (2005).
Understanding and modulating cyclin-dependent kinase inhibitor specificity: molecular modeling and biochemical evaluation of pyrazolopyrimidinones as CDK2/cyclin A and CDK4/cyclin D1 inhibitors.
  J Comput Aided Mol Des, 19, 111-122.  
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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