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PDBsum entry 1w8c

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protein ligands links
Transferase PDB id
1w8c
Jmol
Contents
Protein chain
292 a.a. *
Ligands
N69
Waters ×150
* Residue conservation analysis
PDB id:
1w8c
Name: Transferase
Title: Co-crystal structure of 6-cyclohexylmethoxy-8-isopropyl-9h- purin-2-ylamine and monomeric cdk2
Structure: Cell division protein kinase 2. Chain: a. Synonym: cyclin dependent kinase 2, 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:
2.05Å     R-factor:   0.199     R-free:   0.256
Authors: D.J.Pratt,J.A.Endicott,M.E.M.Noble
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:
20-Sep-04     Release date:   30-Aug-06    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2
Seq:
Struc:
298 a.a.
291 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 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/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.