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PDBsum entry 1ke7

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protein ligands links
Transferase PDB id
1ke7
Jmol
Contents
Protein chain
281 a.a. *
Ligands
LS3
Waters ×107
* Residue conservation analysis
PDB id:
1ke7
Name: Transferase
Title: Cyclin-dependent kinase 2 (cdk2) complexed with 3-{[(2,2- dioxido-1,3-dihydro-2-benzothien-5-yl)amino]methylene}-5- (1,3-oxazol-5-yl)-1,3-dihydro-2h-indol-2-one
Structure: Cell division protein kinase 2. Chain: a. Synonym: cdk2, 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.
Resolution:
2.00Å     R-factor:   0.191     R-free:   0.235
Authors: H.N.Bramson,J.Corona,S.T.Davis,S.H.Dickerson,M.Edelstein, S.V.Frye,R.T.Gampe,A.H.Hassell,L.M.Shewchuk,L.F.Kuyper
Key ref: H.N.Bramson et al. (2001). Oxindole-based inhibitors of cyclin-dependent kinase 2 (CDK2): design, synthesis, enzymatic activities, and X-ray crystallographic analysis. J Med Chem, 44, 4339-4358. PubMed id: 11728181 DOI: 10.1021/jm010117d
Date:
14-Nov-01     Release date:   14-May-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2
Seq:
Struc:
298 a.a.
281 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-dependent protein kinase holoenzyme complex   15 terms 
  Biological process     regulation of gene silencing   27 terms 
  Biochemical function     nucleotide binding     12 terms  

 

 
    reference    
 
 
DOI no: 10.1021/jm010117d J Med Chem 44:4339-4358 (2001)
PubMed id: 11728181  
 
 
Oxindole-based inhibitors of cyclin-dependent kinase 2 (CDK2): design, synthesis, enzymatic activities, and X-ray crystallographic analysis.
H.N.Bramson, J.Corona, S.T.Davis, S.H.Dickerson, M.Edelstein, S.V.Frye, R.T.Gampe, P.A.Harris, A.Hassell, W.D.Holmes, R.N.Hunter, K.E.Lackey, B.Lovejoy, M.J.Luzzio, V.Montana, W.J.Rocque, D.Rusnak, L.Shewchuk, J.M.Veal, D.H.Walker, L.F.Kuyper.
 
  ABSTRACT  
 
Two closely related classes of oxindole-based compounds, 1H-indole-2,3-dione 3-phenylhydrazones and 3-(anilinomethylene)-1,3-dihydro-2H-indol-2-ones, were shown to potently inhibit cyclin-dependent kinase 2 (CDK2). The initial lead compound was prepared as a homologue of the 3-benzylidene-1,3-dihydro-2H-indol-2-one class of kinase inhibitor. Crystallographic analysis of the lead compound bound to CDK2 provided the basis for analogue design. A semiautomated method of ligand docking was used to select compounds for synthesis, and a number of compounds with low nanomolar inhibitory activity versus CDK2 were identified. Enzyme binding determinants for several analogues were evaluated by X-ray crystallography. Compounds in this series inhibited CDK2 with a potency approximately 10-fold greater than that for CDK1. Members of this class of inhibitor cause an arrest of the cell cycle and have shown potential utility in the prevention of chemotherapy-induced alopecia.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21472162 C.R.Reddy, E.Jithender, G.Krishna, G.V.Reddy, and B.Jagadeesh (2011).
A novel acid-catalyzed C5-alkylation of oxindoles using alcohols.
  Org Biomol Chem, 9, 3940-3947.  
20601979 B.V.Silva, N.M.Ribeiro, M.D.Vargas, M.Lanznaster, J.W.Carneiro, R.Krogh, A.D.Andricopulo, L.C.Dias, and A.C.Pinto (2010).
Synthesis, electrochemical studies and anticancer activity of ferrocenyl oxindoles.
  Dalton Trans, 39, 7338-7344.  
20575139 K.Engels, C.Beyer, M.L.Suárez Fernández, F.Bender, M.Gassel, G.Unden, R.J.Marhöfer, J.C.Mottram, and P.M.Selzer (2010).
Inhibition of Eimeria tenella CDK-related kinase 2: From target identification to lead compounds.
  ChemMedChem, 5, 1259-1271.  
18855677 A.Bakan, J.S.Lazo, P.Wipf, K.M.Brummond, and I.Bahar (2008).
Toward a molecular understanding of the interaction of dual specificity phosphatases with substrates: insights from structure-based modeling and high throughput screening.
  Curr Med Chem, 15, 2536-2544.  
18680359 H.R.Lawrence, R.Pireddu, L.Chen, Y.Luo, S.S.Sung, A.M.Szymanski, M.L.Yip, W.C.Guida, S.M.Sebti, J.Wu, and N.J.Lawrence (2008).
Inhibitors of Src homology-2 domain containing protein tyrosine phosphatase-2 (Shp2) based on oxindole scaffolds.
  J Med Chem, 51, 4948-4956.  
17541419 M.P.Mazanetz, and P.M.Fischer (2007).
Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases.
  Nat Rev Drug Discov, 6, 464-479.  
17704657 M.Sassatelli, F.Bouchikhi, B.Aboab, F.Anizon, D.Fabbro, M.Prudhomme, and P.Moreau (2007).
In-vitro antiproliferative activities and kinase inhibitory potencies of glycosyl-isoindigo derivatives.
  Anticancer Drugs, 18, 1069-1074.  
16444268 A.D.Pyle, L.F.Lock, and P.J.Donovan (2006).
Neurotrophins mediate human embryonic stem cell survival.
  Nat Biotechnol, 24, 344-350.  
16632252 C.Kung, D.M.Kenski, K.Krukenberg, H.D.Madhani, and K.M.Shokat (2006).
Selective kinase inhibition by exploiting differential pathway sensitivity.
  Chem Biol, 13, 399-407.  
17205374 G.A.Landrum, J.E.Penzotti, and S.Putta (2006).
Feature-map vectors: a new class of informative descriptors for computational drug discovery.
  J Comput Aided Mol Des, 20, 751-762.  
16584130 J.Sridhar, N.Akula, and N.Pattabiraman (2006).
Selectivity and potency of cyclin-dependent kinase inhibitors.
  AAPS J, 8, E204-E221.  
15738404 C.Kung, D.M.Kenski, S.H.Dickerson, R.W.Howson, L.F.Kuyper, H.D.Madhani, and K.M.Shokat (2005).
Chemical genomic profiling to identify intracellular targets of a multiplex kinase inhibitor.
  Proc Natl Acad Sci U S A, 102, 3587-3592.  
15931503 H.Dureja, and A.K.Madan (2005).
Topochemical models for prediction of cyclin-dependent kinase 2 inhibitory activity of indole-2-ones.
  J Mol Model, 11, 525-531.  
12556199 N.C.Waters, and J.A.Geyer (2003).
Cyclin-dependent protein kinases as therapeutic drug targets for antimalarial drug development.
  Expert Opin Ther Targets, 7, 7.  
11927285 E.A.Sausville (2002).
Complexities in the development of cyclin-dependent kinase inhibitor drugs.
  Trends Mol Med, 8, S32-S37.  
12237154 M.Knockaert, P.Greengard, and L.Meijer (2002).
Pharmacological inhibitors of cyclin-dependent kinases.
  Trends Pharmacol Sci, 23, 417-425.  
12133723 P.L.Toogood (2002).
Progress toward the development of agents to modulate the cell cycle.
  Curr Opin Chem Biol, 6, 472-478.  
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.