1H1S

Structure of human Thr160-phospho CDK2/cyclin A complexed with the inhibitor NU6102


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.286 
  • R-Value Work: 0.236 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structure-Based Design of a Potent Purine-Based Cyclin-Dependent Kinase Inhibitor

Davies, T.G.Bentley, J.Arris, C.E.Boyle, F.T.Curtin, N.J.Endicott, J.A.Gibson, A.E.Golding, B.T.Griffin, R.J.Hardcastle, I.R.Jewsbury, P.Johnson, L.N.Mesguiche, V.Newell, D.R.Noble, M.E.M.Tucker, J.A.Wang, L.Whitfield, H.J.

(2002) Nat Struct Biol 9: 745

  • DOI: https://doi.org/10.1038/nsb842
  • Primary Citation of Related Structures:  
    1H1P, 1H1Q, 1H1R, 1H1S

  • PubMed Abstract: 

    Aberrant control of cyclin-dependent kinases (CDKs) is a central feature of the molecular pathology of cancer. Iterative structure-based design was used to optimize the ATP- competitive inhibition of CDK1 and CDK2 by O(6)-cyclohexylmethylguanines, resulting in O(6)-cyclohexylmethyl-2-(4'- sulfamoylanilino)purine. The new inhibitor is 1,000-fold more potent than the parent compound (K(i) values for CDK1 = 9 nM and CDK2 = 6 nM versus 5,000 nM and 12,000 nM, respectively, for O(6)-cyclohexylmethylguanine). The increased potency arises primarily from the formation of two additional hydrogen bonds between the inhibitor and Asp 86 of CDK2, which facilitate optimum hydrophobic packing of the anilino group with the specificity surface of CDK2. Cellular studies with O(6)-cyclohexylmethyl-2-(4'- sulfamoylanilino) purine demonstrated inhibition of MCF-7 cell growth and target protein phosphorylation, consistent with CDK1 and CDK2 inhibition. The work represents the first successful iterative synthesis of a potent CDK inhibitor based on the structure of fully activated CDK2-cyclin A. Furthermore, the potency of O(6)-cyclohexylmethyl-2-(4'- sulfamoylanilino)purine was both predicted and fully rationalized on the basis of protein-ligand interactions.


  • Organizational Affiliation

    Laboratory of Molecular Biophysics and Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CELL DIVISION PROTEIN KINASE 2
A, C
303Homo sapiensMutation(s): 0 
EC: 2.7.1
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
258Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P20248 (Homo sapiens)
Explore P20248 
Go to UniProtKB:  P20248
PHAROS:  P20248
GTEx:  ENSG00000145386 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP20248
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
4SP
Query on 4SP

Download Ideal Coordinates CCD File 
E [auth A],
F [auth C]
O6-CYCLOHEXYLMETHOXY-2-(4'-SULPHAMOYLANILINO) PURINE
C18 H22 N6 O3 S
OWXORKPNCHJYOF-UHFFFAOYSA-N
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
4SP PDBBind:  1H1S Ki: 6 (nM) from 1 assay(s)
Binding MOAD:  1H1S Ki: 6 (nM) from 1 assay(s)
BindingDB:  1H1S Ki: 6 (nM) from 1 assay(s)
Kd: 1310 (nM) from 1 assay(s)
IC50: min: 5, max: 250 (nM) from 6 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.286 
  • R-Value Work: 0.236 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.23α = 90
b = 135.35β = 90
c = 148.46γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2002-09-19
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance