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PDBsum entry 1pxo

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Transferase PDB id
1pxo
Jmol
Contents
Protein chain
294 a.a. *
Ligands
CK7
Waters ×168
* Residue conservation analysis
PDB id:
1pxo
Name: Transferase
Title: Human cyclin dependent kinase 2 complexed with the inhibitor [4-(2-amino-4-methyl-thiazol-5-yl)-pyrimidin-2- yl]-(3-nitro-phenyl)-amine
Structure: Cell division protein kinase 2. Chain: a. Synonym: p33 protein kinase. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: cdk2. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: hi5.
Resolution:
1.96Å     R-factor:   0.217     R-free:   0.235
Authors: S.Wang,C.Meades,G.Wood,A.Osnowski,S.Anderson,R.Yuill, M.Thomas,M.Mezna,W.Jackson,C.Midgley,G.Griffiths,I.Mcnae, S.Y.Wu,C.Mcinnes,D.Zheleva,M.D.Walkinshaw,P.M.Fischer
Key ref: S.Wang et al. (2004). 2-Anilino-4-(thiazol-5-yl)pyrimidine CDK inhibitors: synthesis, SAR analysis, X-ray crystallography, and biological activity. J Med Chem, 47, 1662-1675. PubMed id: 15027857 DOI: 10.1021/jm0309957
Date:
04-Jul-03     Release date:   13-Apr-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2
Seq:
Struc:
298 a.a.
294 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/jm0309957 J Med Chem 47:1662-1675 (2004)
PubMed id: 15027857  
 
 
2-Anilino-4-(thiazol-5-yl)pyrimidine CDK inhibitors: synthesis, SAR analysis, X-ray crystallography, and biological activity.
S.Wang, C.Meades, G.Wood, A.Osnowski, S.Anderson, R.Yuill, M.Thomas, M.Mezna, W.Jackson, C.Midgley, G.Griffiths, I.Fleming, S.Green, I.McNae, S.Y.Wu, C.McInnes, D.Zheleva, M.D.Walkinshaw, P.M.Fischer.
 
  ABSTRACT  
 
Following the identification through virtual screening of 4-(2,4-dimethyl-thiazol-5-yl)pyrimidin-2-ylamines as moderately potent inhibitors of cyclin-dependent kinase-2 (CDK2), a CDK inhibitor analogue program was initiated. The first aims were to optimize potency and to evaluate the cellular mode of action of lead candidate molecules. Here the synthetic chemistry, the structure-guided design approach, and the structure-activity relationships (SARs) that led to the discovery of 2-anilino-4-(thiazol-5-yl)pyrimidine ATP-antagonistic CDK2 inhibitors, many with very low nM K(i)s against CDK2, are reported. Furthermore, X-ray crystal structures of four representative analogues from our chemical series in complex with CDK2 are presented, and these structures are used to rationalize the observed biochemical SARs. Finally results are reported that show, using the most potent CDK2 inhibitor compound from the current series, that the observed antiproliferative and proapoptotic effects are consistent with cellular CDK2 and CDK9 inhibition.
 

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.  
21463944 O.Chahrour, A.Abdalla, F.Lam, C.Midgley, and S.Wang (2011).
Synthesis and biological evaluation of benzyl styrylsulfonyl derivatives as potent anticancer mitotic inhibitors.
  Bioorg Med Chem Lett, 21, 3066-3069.  
21286784 P.Dobeš, J.Fanfrlík, J.Rezáč, M.Otyepka, and P.Hobza (2011).
Transferable scoring function based on semiempirical quantum mechanical PM6-DH2 method: CDK2 with 15 structurally diverse inhibitors.
  J Comput Aided Mol Des, 25, 223-235.  
21035734 S.Wang, G.Griffiths, C.A.Midgley, A.L.Barnett, M.Cooper, J.Grabarek, L.Ingram, W.Jackson, G.Kontopidis, S.J.McClue, C.McInnes, J.McLachlan, C.Meades, M.Mezna, I.Stuart, M.P.Thomas, D.I.Zheleva, D.P.Lane, R.C.Jackson, D.M.Glover, D.G.Blake, and P.M.Fischer (2010).
Discovery and characterization of 2-anilino-4- (thiazol-5-yl)pyrimidine transcriptional CDK inhibitors as anticancer agents.
  Chem Biol, 17, 1111-1121.
PDB codes: 2xmy 2xnb
19543928 X.Y.Lu, Y.D.Chen, N.Y.Sun, Y.J.Jiang, and Q.D.You (2010).
Molecular-docking-guided 3D-QSAR studies of substituted isoquinoline-1,3-(2H,4H)-diones as cyclin-dependent kinase 4 (CDK4) inhibitors.
  J Mol Model, 16, 163-173.  
19603446 A.Ali, A.Ghosh, R.S.Nathans, N.Sharova, S.O'Brien, H.Cao, M.Stevenson, and T.M.Rana (2009).
Identification of flavopiridol analogues that selectively inhibit positive transcription elongation factor (P-TEFb) and block HIV-1 replication.
  Chembiochem, 10, 2072-2080.  
18037921 P.Taylor, E.Blackburn, Y.G.Sheng, S.Harding, K.Y.Hsin, D.Kan, S.Shave, and M.D.Walkinshaw (2008).
Ligand discovery and virtual screening using the program LIDAEUS.
  Br J Pharmacol, 153, S55-S67.  
17339323 L.Spíchal, V.Krystof, M.Paprskárová, R.Lenobel, J.Styskala, P.Binarová, V.Cenklová, L.De Veylder, D.Inzé, G.Kontopidis, P.M.Fischer, T.Schmülling, and M.Strnad (2007).
Classical anticytokinins do not interact with cytokinin receptors but inhibit cyclin-dependent kinases.
  J Biol Chem, 282, 14356-14363.  
16584130 J.Sridhar, N.Akula, and N.Pattabiraman (2006).
Selectivity and potency of cyclin-dependent kinase inhibitors.
  AAPS J, 8, E204-E221.  
15123247 C.McInnes, S.Wang, S.Anderson, J.O'Boyle, W.Jackson, G.Kontopidis, C.Meades, M.Mezna, M.Thomas, G.Wood, D.P.Lane, and P.M.Fischer (2004).
Structural determinants of CDK4 inhibition and design of selective ATP competitive inhibitors.
  Chem Biol, 11, 525-534.  
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. Where a reference describes a PDB structure, the PDB codes are shown on the right.