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PDBsum entry 4cfn

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protein ligands Protein-protein interface(s) links
Cell cycle PDB id
4cfn
Jmol
Contents
Protein chains
297 a.a.
254 a.a.
Ligands
JYM ×2
DTT ×2
Waters ×555
PDB id:
4cfn
Name: Cell cycle
Title: Structure-based design of c8-substituted o6-cyclohexylmethox cdk1 and 2 inhibitors.
Structure: Cyclin-dependent kinase 2. Chain: a, c. Synonym: cell division protein kinase 2, p33 protein kinase engineered: yes. Other_details: phosphorylated on residue t160. Cyclin-a2. Chain: b, d. Fragment: cdk-activating fragment, residues 175-432. Synonym: cyclin-a.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli b. Expression_system_taxid: 37762.
Resolution:
2.20Å     R-factor:   0.199     R-free:   0.240
Authors: B.Carbain,D.J.Paterson,E.Anscombe,A.Campbell,C.Cano,A.Echali J.Endicott,B.T.Golding,K.Haggerty,I.R.Hardcastle,P.Jewsbury D.R.Newell,M.E.M.Noble,C.Roche,L.Z.Wang,R.Griffin
Key ref: B.Carbain et al. (2014). 8-Substituted O(6)-cyclohexylmethylguanine CDK2 inhibitors: using structure-based inhibitor design to optimize an alternative binding mode. J Med Chem, 57, 56-70. PubMed id: 24304238 DOI: 10.1021/jm401555v
Date:
19-Nov-13     Release date:   18-Dec-13    
PROCHECK
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 Headers
 References

Protein chains
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.
254 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 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/jm401555v J Med Chem 57:56-70 (2014)
PubMed id: 24304238  
 
 
8-Substituted O(6)-cyclohexylmethylguanine CDK2 inhibitors: using structure-based inhibitor design to optimize an alternative binding mode.
B.Carbain, D.J.Paterson, E.Anscombe, A.J.Campbell, C.Cano, A.Echalier, J.A.Endicott, B.T.Golding, K.Haggerty, I.R.Hardcastle, P.J.Jewsbury, D.R.Newell, M.E.Noble, C.Roche, L.Z.Wang, R.J.Griffin.
 
  ABSTRACT  
 
Evaluation of the effects of purine C-8 substitution within a series of CDK1/2-selective O(6)-cyclohexylmethylguanine derivatives revealed that potency decreases initially with increasing size of the alkyl substituent. Structural analysis showed that C-8 substitution is poorly tolerated, and to avoid unacceptable steric interactions, these compounds adopt novel binding modes. Thus, 2-amino-6-cyclohexylmethoxy-8-isopropyl-9H-purine adopts a "reverse" binding mode where the purine backbone has flipped 180°. This provided a novel lead chemotype from which we have designed more potent CDK2 inhibitors using, in the first instance, quantum mechanical energy calculations. Introduction of an ortho-tolyl or ortho-chlorophenyl group at the purine C-8 position restored the potency of these "reverse" binding mode inhibitors to that of the parent 2-amino-6-cyclohexylmethoxy-9H-purine. By contrast, the corresponding 8-(2-methyl-3-sulfamoylphenyl)-purine derivative exhibited submicromolar CDK2-inhibitory activity by virtue of engineered additional interactions with Asp86 and Lys89 in the reversed binding mode, as confirmed by X-ray crystallography.