5ONI

LOW-SALT STRUCTURE OF PROTEIN KINASE CK2 CATALYTIC SUBUNIT (ISOFORM CK2ALPHA) IN COMPLEX WITH THE INDENOINDOLE-TYPE INHIBITOR 4P


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.204 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.176 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Unexpected Binding Mode of a Potent Indeno[1,2-b]indole-Type Inhibitor of Protein Kinase CK2 Revealed by Complex Structures with the Catalytic Subunit CK2 alpha and Its Paralog CK2 alpha '.

Hochscherf, J.Lindenblatt, D.Witulski, B.Birus, R.Aichele, D.Marminon, C.Bouaziz, Z.Le Borgne, M.Jose, J.Niefind, K.

(2017) Pharmaceuticals (Basel) 10

  • DOI: https://doi.org/10.3390/ph10040098
  • Primary Citation of Related Structures:  
    5OMY, 5ONI, 5OOI

  • PubMed Abstract: 

    Protein kinase CK2, a member of the eukaryotic protein kinase superfamily, is associated with cancer and other human pathologies and thus an attractive drug target. The indeno[1,2- b ]indole scaffold is a novel lead structure to develop ATP-competitive CK2 inhibitors. Some indeno[1,2- b ]indole-based CK2 inhibitors additionally obstruct ABCG2, an ABC half transporter overexpressed in breast cancer and co-responsible for drug efflux and resistance. Comprehensive derivatization studies revealed substitutions of the indeno[1,2- b ]indole framework that boost either the CK2 or the ABCG2 selectivity or even support the dual inhibition potential. The best indeno[1,2- b ]indole-based CK2 inhibitor described yet (IC 50 = 25 nM) is 5-isopropyl-4-(3-methylbut-2-enyl-oxy)-5,6,7,8-tetrahydroindeno[1,2- b ]indole-9,10-dione ( 4p ). Herein, we demonstrate the membrane permeability of 4p and describe co-crystal structures of 4p with CK2α and CK2α', the paralogs of human CK2 catalytic subunit. As expected, 4p occupies the narrow, hydrophobic ATP site of CK2α/CK2α', but surprisingly with a unique orientation: its hydrophobic substituents point towards the solvent while its two oxo groups are hydro-gen-bonded to a hidden water molecule. An equivalent water molecule was found in many CK2α structures, but never as a critical mediator of ligand binding. This unexpected binding mode is independent of the interdomain hinge/helix αD region conformation and of the salt content in the crystallization medium.


  • Organizational Affiliation

    Department für Chemie, Institut für Biochemie, Universität zu Köln, Zülpicher Straße 47, D-50674 Köln, Germany. j.hochscherf@uni-koeln.de.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Casein kinase II subunit alpha
A, B
391Homo 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
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
9YE
Query on 9YE

Download Ideal Coordinates CCD File 
C [auth A],
J [auth B]
4-(3-methylbut-2-enoxy)-5-propan-2-yl-7,8-dihydro-6~{H}-indeno[1,2-b]indole-9,10-dione
C23 H25 N O3
IGWUYWFNHIJBBD-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A]
E [auth A]
F [auth A]
G [auth A]
H [auth A]
D [auth A],
E [auth A],
F [auth A],
G [auth A],
H [auth A],
K [auth B],
L [auth B],
M [auth B],
N [auth B],
O [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
BU1
Query on BU1

Download Ideal Coordinates CCD File 
R [auth B]1,4-BUTANEDIOL
C4 H10 O2
WERYXYBDKMZEQL-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
P [auth B],
Q [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
NA
Query on NA

Download Ideal Coordinates CCD File 
I [auth A]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.204 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.176 
  • Space Group: P 43 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 128.453α = 90
b = 128.453β = 90
c = 124.106γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata 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: 2017-12-27
    Type: Initial release
  • Version 1.1: 2024-01-17
    Changes: Data collection, Database references, Refinement description