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PDBsum entry 1oiu

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protein ligands metals Protein-protein interface(s) links
Kinase PDB id
1oiu
Jmol
Contents
Protein chains
297 a.a. *
256 a.a. *
266 a.a. *
Ligands
N76 ×2
SGM ×2
Metals
_MG
Waters ×646
* Residue conservation analysis
PDB id:
1oiu
Name: Kinase
Title: Structure of human thr160-phospho cdk2/cyclin a complexed with a 6-cyclohexylmethyloxy-2-anilino-purine inhibitor
Structure: Cell division protein kinase 2. Chain: a, c. Synonym: p33 protein kinase, cdk2. Engineered: yes. Other_details: phosphorylated on thr160. Cyclin a2. Chain: b, d. Fragment: residues 174-432. Synonym: cyclin a, ccna2, ccna, ccn1.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562
Biol. unit: Dimer (from PDB file)
Resolution:
2.0Å     R-factor:   0.215     R-free:   0.253
Authors: D.J.Pratt,J.A.Endicott,M.E.M.Noble
Key ref: I.R.Hardcastle et al. (2004). N2-substituted O6-cyclohexylmethylguanine derivatives: potent inhibitors of cyclin-dependent kinases 1 and 2. J Med Chem, 47, 3710-3722. PubMed id: 15239650 DOI: 10.1021/jm0311442
Date:
26-Jun-03     Release date:   13-Jul-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2
Seq:
Struc:
298 a.a.
297 a.a.*
Protein chains
Pfam   ArchSchema ?
P20248  (CCNA2_HUMAN) -  Cyclin-A2
Seq:
Struc:
432 a.a.
256 a.a.
Protein chain
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2
Seq:
Struc:
298 a.a.
266 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chains A, C: 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   30 terms 
  Biochemical function     nucleotide binding     13 terms  

 

 
    reference    
 
 
DOI no: 10.1021/jm0311442 J Med Chem 47:3710-3722 (2004)
PubMed id: 15239650  
 
 
N2-substituted O6-cyclohexylmethylguanine derivatives: potent inhibitors of cyclin-dependent kinases 1 and 2.
I.R.Hardcastle, C.E.Arris, J.Bentley, F.T.Boyle, Y.Chen, N.J.Curtin, J.A.Endicott, A.E.Gibson, B.T.Golding, R.J.Griffin, P.Jewsbury, J.Menyerol, V.Mesguiche, D.R.Newell, M.E.Noble, D.J.Pratt, L.Z.Wang, H.J.Whitfield.
 
  ABSTRACT  
 
The adenosine 5'-triphosphate (ATP) competitive cyclin-dependent kinase inhibitor O(6)-cyclohexylmethylguanine (NU2058, 1) has been employed as the lead in a structure-based drug discovery program resulting in the discovery of the potent CDK1 and -2 inhibitor NU6102 (3, IC(50) = 9.5 nM and 5.4 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively). The SAR for this series have been explored further by the synthesis and evaluation of 45 N(2)-substituted analogues of NU2058. These studies have confirmed the requirement for the hydrogen bonding N(2)-NH group and the requirement for an aromatic N(2)-substituent to confer potency in the series. Additional potency is conferred by the presence of a group capable of donating a hydrogen bond at the 4'-position, for example, the 4'-hydroxy derivative (25, IC(50) = 94 nM and 69 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively), 4'-monomethylsulfonamide derivative (28, IC(50) = 9 nM and 7.0 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively), and 4'-carboxamide derivative (34, IC(50) = 67 nM and 64 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively). X-ray crystal structures have been obtained for key compounds and have been used to explain the observed trends in activity.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20448906 C.Wong, R.J.Griffin, I.R.Hardcastle, J.S.Northen, L.Z.Wang, and B.T.Golding (2010).
Synthesis of sulfonamide-based kinase inhibitors from sulfonates by exploiting the abrogated SN2 reactivity of 2,2,2-trifluoroethoxysulfonates.
  Org Biomol Chem, 8, 2457-2464.  
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.  
20237920 O.Sperandio, L.Mouawad, E.Pinto, B.O.Villoutreix, D.Perahia, and M.A.Miteva (2010).
How to choose relevant multiple receptor conformations for virtual screening: a test case of Cdk2 and normal mode analysis.
  Eur Biophys J, 39, 1365-1372.  
19194508 J.Xiang, H.Yang, C.Che, H.Zou, H.Yang, Y.Wei, J.Quan, H.Zhang, Z.Yang, and S.Lin (2009).
Identifying tumor cell growth inhibitors by combinatorial chemistry and zebrafish assays.
  PLoS ONE, 4, e4361.  
17599054 A.C.Rigas, C.N.Robson, and N.J.Curtin (2007).
Therapeutic potential of CDK inhibitor NU2058 in androgen-independent prostate cancer.
  Oncogene, 26, 7611-7619.  
17571187 F.Marchetti, K.L.Sayle, J.Bentley, W.Clegg, N.J.Curtin, J.A.Endicott, B.T.Golding, R.J.Griffin, K.Haggerty, R.W.Harrington, V.Mesguiche, D.R.Newell, M.E.Noble, R.J.Parsons, D.J.Pratt, L.Z.Wang, and I.R.Hardcastle (2007).
Structure-based design of 2-arylamino-4-cyclohexylmethoxy-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinase 2.
  Org Biomol Chem, 5, 1577-1585.  
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.  
16584130 J.Sridhar, N.Akula, and N.Pattabiraman (2006).
Selectivity and potency of cyclin-dependent kinase inhibitors.
  AAPS J, 8, E204-E221.  
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.