5CYI

CDK2/Cyclin A covalent complex with 6-(cyclohexylmethoxy)-N-(4-(vinylsulfonyl)phenyl)-9H-purin-2-amine (NU6300)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.255 
  • R-Value Work: 0.227 
  • R-Value Observed: 0.228 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Identification and Characterization of an Irreversible Inhibitor of CDK2.

Anscombe, E.Meschini, E.Mora-Vidal, R.Martin, M.P.Staunton, D.Geitmann, M.Danielson, U.H.Stanley, W.A.Wang, L.Z.Reuillon, T.Golding, B.T.Cano, C.Newell, D.R.Noble, M.E.Wedge, S.R.Endicott, J.A.Griffin, R.J.

(2015) Chem Biol 22: 1159-1164

  • DOI: https://doi.org/10.1016/j.chembiol.2015.07.018
  • Primary Citation of Related Structures:  
    5CYI

  • PubMed Abstract: 

    Irreversible inhibitors that modify cysteine or lysine residues within a protein kinase ATP binding site offer, through their distinctive mode of action, an alternative to ATP-competitive agents. 4-((6-(Cyclohexylmethoxy)-9H-purin-2-yl)amino)benzenesulfonamide (NU6102) is a potent and selective ATP-competitive inhibitor of CDK2 in which the sulfonamide moiety is positioned close to a pair of lysine residues. Guided by the CDK2/NU6102 structure, we designed 6-(cyclohexylmethoxy)-N-(4-(vinylsulfonyl)phenyl)-9H-purin-2-amine (NU6300), which binds covalently to CDK2 as shown by a co-complex crystal structure. Acute incubation with NU6300 produced a durable inhibition of Rb phosphorylation in SKUT-1B cells, consistent with it acting as an irreversible CDK2 inhibitor. NU6300 is the first covalent CDK2 inhibitor to be described, and illustrates the potential of vinyl sulfones for the design of more potent and selective compounds.


  • 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
303Homo sapiensMutation(s): 0 
Gene Names: CDK2CDKN2
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
260Homo sapiensMutation(s): 0 
Gene Names: CCNA2CCN1CCNA
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
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
55S
Query on 55S

Download Ideal Coordinates CCD File 
E [auth A],
F [auth C]
6-(cyclohexylmethoxy)-N-[4-(ethylsulfonyl)phenyl]-9H-purin-2-amine
C20 H25 N5 O3 S
SIKZOJIFMBUYSK-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
TPO
Query on TPO
A, C
L-PEPTIDE LINKINGC4 H10 N O6 PTHR
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.255 
  • R-Value Work: 0.227 
  • R-Value Observed: 0.228 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.286α = 90
b = 135.289β = 90
c = 148.673γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Medical Research Council (United Kingdom)United KingdomG0901526
Cancer Research UKUnited KingdomC240/A15751
European UnionUnited KingdomFP6-PROKINASE

Revision History  (Full details and data files)

  • Version 1.0: 2015-09-16
    Type: Initial release
  • Version 1.1: 2015-09-30
    Changes: Database references
  • Version 1.2: 2017-08-30
    Changes: Author supporting evidence
  • Version 1.3: 2024-01-10
    Changes: Data collection, Database references, Refinement description