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PDBsum entry 4aua

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Transferase PDB id
4aua
Jmol
Contents
Protein chain
256 a.a.
Ligands
4AU
Waters ×86
PDB id:
4aua
Name: Transferase
Title: Liganded x-ray crystal structure of cyclin dependent kinase
Structure: Cyclin-dependent kinase 6. Chain: a. Fragment: kinase domain, residues 1-301. Synonym: cell division protein kinase 6, serine/threonine-p kinase plstire. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108
Resolution:
2.31Å     R-factor:   0.210     R-free:   0.277
Authors: Y.S.Cho,H.Angove,C.Brain,C.H.T.Chen,R.Cheng,R.Chopra,K.Chung M.Congreve,C.Dagostin,D.Davis,R.Feltell,J.Giraldes,S.Hiscoc S.Kovats,B.Lagu,K.Lewry,A.Loo,Y.Lu,M.Luzzio,W.Maniara,R.Mcm P.Mortenson,R.Benning,M.Oreilly,D.Rees,J.Shen,T.Smith,Y.Wan G.Williams,A.Woolford,W.Wrona,M.Xu,F.Yang,S.Howard
Key ref: Y.S.Cho et al. (2012). Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors. ACS Med Chem Lett, 3, 445-449. PubMed id: 24900493 DOI: 10.1021/ml200241a
Date:
15-May-12     Release date:   06-Feb-13    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q00534  (CDK6_HUMAN) -  Cyclin-dependent kinase 6
Seq:
Struc:
326 a.a.
256 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     cell projection   7 terms 
  Biological process     type B pancreatic cell development   35 terms 
  Biochemical function     nucleotide binding     10 terms  

 

 
    reference    
 
 
DOI no: 10.1021/ml200241a ACS Med Chem Lett 3:445-449 (2012)
PubMed id: 24900493  
 
 
Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors.
Y.S.Cho, H.Angove, C.Brain, C.H.Chen, H.Cheng, R.Cheng, R.Chopra, K.Chung, M.Congreve, C.Dagostin, D.J.Davis, R.Feltell, J.Giraldes, S.D.Hiscock, S.Kim, S.Kovats, B.Lagu, K.Lewry, A.Loo, Y.Lu, M.Luzzio, W.Maniara, R.McMenamin, P.N.Mortenson, R.Benning, M.O'Reilly, D.C.Rees, J.Shen, T.Smith, Y.Wang, G.Williams, A.J.Woolford, W.Wrona, M.Xu, F.Yang, S.Howard.
 
  ABSTRACT  
 
Herein, we describe the discovery of potent and highly selective inhibitors of both CDK4 and CDK6 via structure-guided optimization of a fragment-based screening hit. CDK6 X-ray crystallography and pharmacokinetic data steered efforts in identifying compound 6, which showed >1000-fold selectivity for CDK4 over CDKs 1 and 2 in an enzymatic assay. Furthermore, 6 demonstrated in vivo inhibition of pRb-phosphorylation and oral efficacy in a Jeko-1 mouse xenograft model.