4BCM

Structure of CDK2 in complex with cyclin A and a 2-amino-4-heteroaryl- pyrimidine inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.45 Å
  • R-Value Free: 0.258 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.198 

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Ligand Structure Quality Assessment 


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Literature

Comparative Structural and Functional Studies of 4-(Thiazol- 5-Yl)-2-(Phenylamino)Pyrimidine-5-Carbonitrile Cdk9 Inhibitors Suggest the Basis for Isotype Selectivity.

Hole, A.J.Baumli, S.Shao, H.Shi, S.Pepper, C.Fischer, P.M.Wang, S.Endicott, J.A.Noble, M.E.M.

(2013) J Med Chem 56: 660

  • DOI: https://doi.org/10.1021/jm301495v
  • Primary Citation of Related Structures:  
    4BCF, 4BCH, 4BCI, 4BCJ, 4BCK, 4BCM, 4BCN, 4BCO, 4BCQ

  • PubMed Abstract: 

    Cyclin-dependent kinase 9/cyclin T, the protein kinase heterodimer that constitutes positive transcription elongation factor b, is a well-validated target for treatment of several diseases, including cancer and cardiac hypertrophy. In order to aid inhibitor design and rationalize the basis for CDK9 selectivity, we have studied the CDK-binding properties of six different members of a 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile series that bind to both CDK9/cyclin T and CDK2/cyclin A. We find that for a given CDK, the melting temperature of a CDK/cyclin/inhibitor complex correlates well with inhibitor potency, suggesting that differential scanning fluorimetry (DSF) is a useful orthogonal measure of inhibitory activity for this series. We have used DSF to demonstrate that the binding of these compounds is independent of the presence or absence of the C-terminal tail region of CDK9, unlike the binding of the CDK9-selective inhibitor 5,6-dichlorobenzimidazone-1-β-d-ribofuranoside (DRB). Finally, on the basis of 11 cocrystal structures bound to CDK9/cyclin T or CDK2/cyclin A, we conclude that selective inhibition of CDK9/cyclin T by members of the 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile series results from the relative malleability of the CDK9 active site rather than from the formation of specific polar contacts.


  • Organizational Affiliation

    Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CYCLIN-DEPENDENT KINASE 2
A, C
301Homo sapiensMutation(s): 0 
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
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
CYCLIN-A2262Homo 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
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
CYCLIN-A2262Homo 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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
T7Z
Query on T7Z

Download Ideal Coordinates CCD File 
E [auth A],
G [auth C]
4-(4-methyl-2-methylimino-3H-1,3-thiazol-5-yl)-2-[(4-methyl-3-morpholin-4-ylsulfonyl-phenyl)amino]pyrimidine-5-carbonitrile
C21 H23 N7 O3 S2
SSEDQERECATUBR-UHFFFAOYSA-N
SGM
Query on SGM

Download Ideal Coordinates CCD File 
F [auth B],
H [auth D]
MONOTHIOGLYCEROL
C3 H8 O2 S
PJUIMOJAAPLTRJ-GSVOUGTGSA-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
T7Z PDBBind:  4BCM Ki: 123 (nM) from 1 assay(s)
Binding MOAD:  4BCM Ki: 123 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.45 Å
  • R-Value Free: 0.258 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.198 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.07α = 90
b = 135.41β = 90
c = 148.63γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-03-06
    Type: Initial release