spacer
spacer

PDBsum entry 3ddq

Go to PDB code: 
protein ligands Protein-protein interface(s) links
Transferase/cell cycle PDB id
3ddq
Jmol
Contents
Protein chains
297 a.a. *
262 a.a. *
267 a.a. *
Ligands
RRC ×2
SGM ×3
Waters ×823
* Residue conservation analysis
PDB id:
3ddq
Name: Transferase/cell cycle
Title: Structure of phosphorylated thr160 cdk2/cyclin a in complex with the inhibitor roscovitine
Structure: Cell division protein kinase 2. Chain: a, c. Fragment: cdk2. Synonym: p33 protein kinase. Engineered: yes. Cyclin-a2. Chain: b, d. Fragment: unp residues 169-430. Synonym: cyclin-a.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: cdk2. Expressed in: escherichia coli. Bos taurus. Bovine. Organism_taxid: 9913. Gene: ccna2, ccna.
Resolution:
1.80Å     R-factor:   0.195     R-free:   0.229
Authors: A.Echalier,J.A.Endicott
Key ref: K.Bettayeb et al. (2008). CR8, a potent and selective, roscovitine-derived inhibitor of cyclin-dependent kinases. Oncogene, 27, 5797-5807. PubMed id: 18574471
Date:
06-Jun-08     Release date:   22-Jul-08    
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
No UniProt id for this chain
Struc: 262 a.a.
Protein chain
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2
Seq:
Struc:
298 a.a.
267 a.a.*
Key:    PfamA 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    
 
 
Oncogene 27:5797-5807 (2008)
PubMed id: 18574471  
 
 
CR8, a potent and selective, roscovitine-derived inhibitor of cyclin-dependent kinases.
K.Bettayeb, N.Oumata, A.Echalier, Y.Ferandin, J.A.Endicott, H.Galons, L.Meijer.
 
  ABSTRACT  
 
Among the ten pharmacological inhibitors of cyclin-dependent kinases (CDKs) currently in clinical trials, the purine roscovitine (CYC202, Seliciclib) is undergoing phase 2 trials against non-small-cell lung and nasopharyngeal cancers. An extensive medicinal chemistry study, designed to generate more potent analogues of roscovitine, led to the identification of an optimal substitution at the N6 position (compound CR8). An extensive selectivity study (108 kinases) highlights the exquisite selectivity of CR8 for CDK1/2/3/5/7/9. CR8 was 2- to 4-fold more potent than (R)-roscovitine at inhibiting these kinases. Cocrystal structures of (R)-CR8 and (R)-roscovitine with pCDK2/cyclin A showed that both inhibitors adopt essentially identical positions. The cellular effects of CR8 and (R)-roscovitine were investigated in human neuroblastoma SH-SY5Y cells. CR8 inhibited the phosphorylation of CDK1 and 9 substrates, with a 25-50 times higher potency compared to (R)-roscovitine. CR8 was consistently more potent than (R)-roscovitine at inducing apoptotic cell death parameters: 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium reduction (40-fold), lactate dehydrogenase release (35-fold), caspases activation (68-fold) and poly-(ADP-ribose)polymerase cleavage (50-fold). This improved cell death-inducing activity of CR8 over (R)-roscovitine was observed in 25 different cell lines. Altogether these results show that second-generation analogues of (R)-roscovitine can be designed with improved antitumor potential.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21333571 C.Fang, Z.Xiao, and Z.Guo (2011).
Generation and validation of the first predictive pharmacophore model for cyclin-dependent kinase 9 inhibitors.
  J Mol Graph Model, 29, 800-808.  
20013135 B.Zhang, Z.C.Su, T.E.Tay, and V.B.Tan (2010).
Mechanism of CDK5 activation revealed by steered molecular dynamics simulations and energy calculations.
  J Mol Model, 16, 1159-1168.  
20052971 C.Almeida, E.Eguereva, S.Kehraus, C.Siering, and G.M.König (2010).
Hydroxylated sclerosporin derivatives from the marine-derived fungus Cadophora malorum.
  J Nat Prod, 73, 476-478.  
19296866 L.N.Johnson (2009).
Protein kinase inhibitors: contributions from structure to clinical compounds.
  Q Rev Biophys, 42, 1.  
19568282 S.Lapenna, and A.Giordano (2009).
Cell cycle kinases as therapeutic targets for cancer.
  Nat Rev Drug Discov, 8, 547-566.  
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.