3R0T

Crystal structure of human protein kinase CK2 alpha subunit in complex with the inhibitor CX-5279


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.160 
  • R-Value Observed: 0.163 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Unprecedented selectivity and structural determinants of a new class of protein kinase CK2 inhibitors in clinical trials for the treatment of cancer.

Battistutta, R.Cozza, G.Pierre, F.Papinutto, E.Lolli, G.Sarno, S.O'Brien, S.E.Siddiqui-Jain, A.Haddach, M.Anderes, K.Ryckman, D.M.Meggio, F.Pinna, L.A.

(2011) Biochemistry 50: 8478-8488

  • DOI: https://doi.org/10.1021/bi2008382
  • Primary Citation of Related Structures:  
    3PE1, 3PE2, 3R0T

  • PubMed Abstract: 

    5-(3-Chlorophenylamino)benzo[c][2,6]naphthyridine-8-carboxylic acid (CX-4945), the first clinical stage inhibitor of protein kinase CK2 for the treatment of cancer, is representative of a new class of CK2 inhibitors with K(i) values in the low nanomolar range and unprecedented selectivity versus other kinases. Here we present the crystal structure of the complexes of CX-4945 and two analogues (CX-5011 and CX-5279) with the catalytic subunit of human CK2. Consistent with their ATP-competitive mode of inhibition, all three compounds bind in the active site of CK2 (type I inhibitors). The tricyclic scaffold of the inhibitors superposes on the adenine of ATP, establishing multiple hydrophobic interactions with the binding cavity. The more extended scaffold, as compared to that of ATP, allows the carboxylic function, shared by all three ligands, to penetrate into the deepest part of the active site where it makes interactions with conserved water W1 and Lys-68, thus accounting for the crucial role of this negatively charged group in conferring high potency to this class of inhibitors. The presence of a pyrimidine in CX-5011 and in CX-5279 instead of a pyridine (as in CX-4945) ring is likely to account for the higher specificity of these compounds whose Gini coefficients, calculated by profiling them against panels of 102 and/or 235 kinases, are significantly higher than that of CX-4945 (0.735 and 0.755, respectively, vs 0.615), marking the highest selectivity ever reported for CK2 inhibitors.


  • Organizational Affiliation

    Venetian Institute of Molecular Medicine, Via G. Orus 2, 35129 Padova, Italy. [email protected]


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Casein kinase II subunit alpha337Homo sapiensMutation(s): 0 
Gene Names: CSNK2A1CK2A1
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for P68400 (Homo sapiens)
Explore P68400 
Go to UniProtKB:  P68400
PHAROS:  P68400
GTEx:  ENSG00000101266 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP68400
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FU9
Query on FU9

Download Ideal Coordinates CCD File 
B [auth A]3-(cyclopropylamino)-5-{[3-(trifluoromethyl)phenyl]amino}pyrimido[4,5-c]quinoline-8-carboxylic acid
C22 H16 F3 N5 O2
UXZATHOFDZQOMY-UHFFFAOYSA-N
PEG
Query on PEG

Download Ideal Coordinates CCD File 
G [auth A]DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A],
E [auth A],
F [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
EDO
Query on EDO

Download Ideal Coordinates CCD File 
H [auth A]
I [auth A]
J [auth A]
K [auth A]
L [auth A]
H [auth A],
I [auth A],
J [auth A],
K [auth A],
L [auth A],
M [auth A],
N [auth A],
O [auth A],
P [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
FU9 BindingDB:  3R0T IC50: min: 9, max: 750 (nM) from 3 assay(s)
PDBBind:  3R0T IC50: 0.91 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.160 
  • R-Value Observed: 0.163 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.352α = 90
b = 46.184β = 111.51
c = 63.3γ = 90
Software Package:
Software NamePurpose
SCALAdata processing
PHENIXrefinement
PDB_EXTRACTdata extraction
Elettradata collection
XDSdata reduction
SCALAdata scaling
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: 2011-12-07
    Type: Initial release
  • Version 1.1: 2014-10-29
    Changes: Structure summary
  • Version 1.2: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description