3DOG

Structure of Thr 160 phosphorylated CDK2/cyclin A in complex with the inhibitor N-&-N1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.199 

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Literature

N-&-N, a new class of cell death-inducing kinase inhibitors derived from the purine roscovitine.

Bettayeb, K.Sallam, H.Ferandin, Y.Popowycz, F.Fournet, G.Hassan, M.Echalier, A.Bernard, P.Endicott, J.Joseph, B.Meijer, L.

(2008) Mol Cancer Ther 7: 2713-2724

  • DOI: https://doi.org/10.1158/1535-7163.MCT-08-0080
  • Primary Citation of Related Structures:  
    3DOG

  • PubMed Abstract: 

    Cyclin-dependent kinases (CDKs) and their regulators show frequent abnormalities in tumors. Ten low molecular weight pharmacologic inhibitors of CDKs are currently in clinical trials against various cancers, including the 2,6,9-trisubstituted purine (R)-roscovitine (CYC202/Seliciclib). We here report the characterization of N-&-N1, a bioisoster of roscovitine displaying improved antitumoral properties. N-&-N1 shows exquisite selectivity for CDKs, with 2- to 3-fold enhanced potency compared with (R)-roscovitine. Inhibition of retinoblastoma protein phosphorylation and RNA polymerase II Ser2 phosphorylation in neuroblastoma SH-SY5Y cells exposed to N-&-N1 indicates that N-&-N1 is able to inhibit CDKs in a cellular context. N-&-N1 also down-regulates the expression of RNA polymerase. Cocrystal structures of N-&-N1 and (R)-roscovitine in complex with CDK2/cyclin A reveal that both inhibitors adopt similar binding modes. A competitive assay shows that, compared with (R)-roscovitine, N-&-N1 has reduced affinity for Erk2 and pyridoxal kinase. N-&-N1 triggers cell death in a panel of diverse cell lines. Cell death is accompanied by events characteristic of apoptosis: cytochrome c release, activation of effector caspases, and poly(ADP-ribose) polymerase cleavage. Induction of p53 and p21CIP1 and down-regulation of the Mcl-1 antiapoptotic factor were also observed. Studies in mice show that N-&-N1 has pharmacokinetics properties similar to those of (R)-roscovitine. Altogether, these results show that analogues of (R)-roscovitine can be designed with improved antitumor potential.


  • Organizational Affiliation

    Centre National de la Recherche Scientifique, Protein Phosphorylation and Human Disease Group, UPS2682, Station Biologique, B.P. 74, 29682 Roscoff cedex, Bretagne, France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cell division protein kinase 2
A, C
299Homo sapiensMutation(s): 0 
Gene Names: CDK2
EC: 2.7.11.22
UniProt & NIH Common Fund Data Resources
Find proteins for P24941 (Homo sapiens)
Explore P24941 
Go to UniProtKB:  P24941
PHAROS:  P24941
GTEx:  ENSG00000123374 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP24941
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Cyclin-A2
B, D
264Bos taurusMutation(s): 0 
Gene Names: CCNA2CCNA
UniProt
Find proteins for P30274 (Bos taurus)
Explore P30274 
Go to UniProtKB:  P30274
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP30274
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
TPO
Query on TPO
A, C
L-PEPTIDE LINKINGC4 H10 N O6 PTHR
Binding Affinity Annotations 
IDSourceBinding Affinity
NNN PDBBind:  3DOG IC50: 40 (nM) from 1 assay(s)
BindingDB:  3DOG IC50: min: 26, max: 43 (nM) from 4 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.199 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.42α = 90
b = 133.489β = 90
c = 147.996γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
ADSCdata collection
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-09-30
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance