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PDBsum entry 1h0w

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Transferase PDB id
1h0w
Jmol
Contents
Protein chain
283 a.a. *
Ligands
207
Waters ×133
* Residue conservation analysis
PDB id:
1h0w
Name: Transferase
Title: Human cyclin dependent protein kinase 2 in complex with the inhibitor 2-amino-6-[cyclohex-3-enyl]methoxypurine
Structure: Cell division protein kinase 2. Chain: a. Synonym: human cyclin-dependent kinase 2, 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:
2.1Å     R-factor:   0.214     R-free:   0.287
Authors: A.E.Gibson,C.E.Arris,J.Bentley,F.T.Boyle,N.J.Curtin, T.G.Davies,J.A.Endicott,B.T.Golding,S.Grant,R.J.Griffin, P.Jewsbury,L.N.Johnson,V.Mesguiche,D.R.Newell,M.E.M.Noble, J.A.Tucker,H.J.Whitfield
Key ref: A.E.Gibson et al. (2002). Probing the ATP ribose-binding domain of cyclin-dependent kinases 1 and 2 with O(6)-substituted guanine derivatives. J Med Chem, 45, 3381-3393. PubMed id: 12139449 DOI: 10.1021/jm020056z
Date:
27-Jun-02     Release date:   27-Jun-03    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2
Seq:
Struc:
298 a.a.
283 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/jm020056z J Med Chem 45:3381-3393 (2002)
PubMed id: 12139449  
 
 
Probing the ATP ribose-binding domain of cyclin-dependent kinases 1 and 2 with O(6)-substituted guanine derivatives.
A.E.Gibson, C.E.Arris, J.Bentley, F.T.Boyle, N.J.Curtin, T.G.Davies, J.A.Endicott, B.T.Golding, S.Grant, R.J.Griffin, P.Jewsbury, L.N.Johnson, V.Mesguiche, D.R.Newell, M.E.Noble, J.A.Tucker, H.J.Whitfield.
 
  ABSTRACT  
 
O(6)-substituted guanines are adenosine 5'-triphosphate (ATP) competitive inhibitors of CDK1/cyclin B1 and CDK2/cyclin A, the O(6) substituent occupying the kinase ribose binding site. Fifty-eight O(6)-substituted guanines were prepared to probe the ribose pocket, and the structures of four representative compounds bound to monomeric CDK2 were determined by X-ray crystallography. Optimum binding occurs with a moderately sized aliphatic O(6) substituent that packs tightly against the hydrophobic patch presented by the glycine loop, centered on Val18, an interaction promoted by the conformational restraints imposed in a cyclohexylmethyl or cyclohexenylmethyl ring. Structure-based design generated (R)-(2-amino-9H-purin-6-yloxymethyl)pyrrolidin-2-one (56), which reproduces the reported hydrogen bonds formed between ATP and Asp86 and Gln131 but failed to improve inhibitory potency. Thus, the parent compound O(6)-cyclohexylmethylguanine (NU2058, 25) is the preferred starting point for exploring other areas of the kinase active site.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20448898 F.Marchetti, C.Cano, N.J.Curtin, B.T.Golding, R.J.Griffin, K.Haggerty, D.R.Newell, R.J.Parsons, S.L.Payne, L.Z.Wang, and I.R.Hardcastle (2010).
Synthesis and biological evaluation of 5-substituted O4-alkylpyrimidines as CDK2 inhibitors.
  Org Biomol Chem, 8, 2397-2407.  
17085505 J.H.Alzate-Morales, R.Contreras, A.Soriano, I.Tuñon, and E.Silla (2007).
A computational study of the protein-ligand interactions in CDK2 inhibitors: using quantum mechanics/molecular mechanics interaction energy as a predictor of the biological activity.
  Biophys J, 92, 430-439.  
16374623 A.T.García-Sosa, and R.L.Mancera (2006).
The effect of a tightly bound water molecule on scaffold diversity in the computer-aided de novo ligand design of CDK2 inhibitors.
  J Mol Model, 12, 422-431.  
16374872 J.Bonet, G.Caltabiano, A.K.Khan, M.A.Johnston, C.Corbí, A.Gómez, X.Rovira, J.Teyra, and J.Villà-Freixa (2006).
The role of residue stability in transient protein-protein interactions involved in enzymatic phosphate hydrolysis. A computational study.
  Proteins, 63, 65-77.  
16584130 J.Sridhar, N.Akula, and N.Pattabiraman (2006).
Selectivity and potency of cyclin-dependent kinase inhibitors.
  AAPS J, 8, E204-E221.  
16575928 P.Dobes, M.Otyepka, M.Strnad, and P.Hobza (2006).
Interaction energies for the purine inhibitor roscovitine with cyclin-dependent kinase 2: correlated ab initio quantum-chemical, DFT and empirical calculations.
  Chemistry, 12, 4297-4304.  
15993080 L.Havlicek, K.Fuksova, V.Krystof, M.Orsag, B.Vojtesek, and M.Strnad (2005).
8-Azapurines as new inhibitors of cyclin-dependent kinases.
  Bioorg Med Chem, 13, 5399-5407.  
15723259 M.L.Fishel, M.P.Gamcsik, S.M.Delaney, E.G.Zuhowski, V.M.Maher, T.Karrison, R.C.Moschel, M.J.Egorin, and M.E.Dolan (2005).
Role of glutathione and nucleotide excision repair in modulation of cisplatin activity with O6-benzylguanine.
  Cancer Chemother Pharmacol, 55, 333-342.  
12244298 T.G.Davies, J.Bentley, C.E.Arris, F.T.Boyle, N.J.Curtin, J.A.Endicott, A.E.Gibson, B.T.Golding, R.J.Griffin, I.R.Hardcastle, P.Jewsbury, L.N.Johnson, V.Mesguiche, D.R.Newell, M.E.Noble, J.A.Tucker, L.Wang, and H.J.Whitfield (2002).
Structure-based design of a potent purine-based cyclin-dependent kinase inhibitor.
  Nat Struct Biol, 9, 745-749.
PDB codes: 1h1p 1h1q 1h1r 1h1s
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