5CS6

Crystal Structure of CK2alpha with Compound 3 bound


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.88 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.206 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Specific inhibition of CK2 alpha from an anchor outside the active site.

Brear, P.De Fusco, C.Hadje Georgiou, K.Francis-Newton, N.J.Stubbs, C.J.Sore, H.F.Venkitaraman, A.R.Abell, C.Spring, D.R.Hyvonen, M.

(2016) Chem Sci 7: 6839-6845

  • DOI: https://doi.org/10.1039/c6sc02335e
  • Primary Citation of Related Structures:  
    5CLP, 5CS6, 5CSH, 5CSP, 5CSV, 5CU3, 5CU4, 5CU6, 5CVF, 5CVG, 5CVH

  • PubMed Abstract: 

    The development of selective inhibitors of protein kinases is challenging because of the significant conservation of the ATP binding site. Here, we describe a new mechanism by which the protein kinase CK2α can be selectively inhibited using features outside the ATP site. We have identified a new binding site for small molecules on CK2α adjacent to the ATP site and behind the αD loop, termed the αD pocket. An elaborated fragment anchored in this site has been linked with a low affinity fragment binding in the ATP site, creating a novel and selective inhibitor (CAM4066) that binds CK2α with a K d of 320 nM and shows significantly improved selectivity compared to other CK2α inhibitors. CAM4066 shows target engagement in several cell lines and similar potency to clinical trial candidate CX4945. Our data demonstrate that targeting a poorly conserved, cryptic pocket allows inhibition of CK2α via a novel mechanism, enabling the development of a new generation of selective CK2α inhibitors.


  • Organizational Affiliation

    Department of Biochemistry , University of Cambridge , 80 Tennis Court Road , Cambridge CB2 1GA , UK . Email: [email protected].


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Casein kinase II subunit alpha
A, B
352Homo sapiensMutation(s): 1 
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 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
K82
Query on K82

Download Ideal Coordinates CCD File 
F [auth A],
G [auth A],
H [auth A],
I [auth A]
1-(3-chloro-4-propoxyphenyl)methanamine
C10 H14 Cl N O
BVPLWEHIQIGKSU-UHFFFAOYSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
J [auth A]PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
ACT
Query on ACT

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A],
E [auth A],
K [auth B]
ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
K82 BindingDB:  5CS6 IC50: 3.00e+6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.88 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.206 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 64.5α = 90
b = 68.848β = 90
c = 335.872γ = 90
Software Package:
Software NamePurpose
Aimlessdata scaling
PHASERphasing
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction
XDSdata reduction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Wellcome TrustUnited Kingdom090340/Z/09/Z

Revision History  (Full details and data files)

  • Version 1.0: 2016-07-27
    Type: Initial release
  • Version 1.1: 2017-05-10
    Changes: Database references
  • Version 1.2: 2024-01-10
    Changes: Data collection, Database references, Refinement description