5CVH

Crystal Structure of CK2alpha


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.204 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 2.1 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
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  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
IHP
Query on IHP

Download Ideal Coordinates CCD File 
D [auth A],
H [auth B]
INOSITOL HEXAKISPHOSPHATE
C6 H18 O24 P6
IMQLKJBTEOYOSI-GPIVLXJGSA-N
ADP
Query on ADP

Download Ideal Coordinates CCD File 
C [auth A],
G [auth B]
ADENOSINE-5'-DIPHOSPHATE
C10 H15 N5 O10 P2
XTWYTFMLZFPYCI-KQYNXXCUSA-N
ACT
Query on ACT

Download Ideal Coordinates CCD File 
F [auth A]ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
MG
Query on MG

Download Ideal Coordinates CCD File 
E [auth A],
I [auth B]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.204 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 64.495α = 90
b = 68.69β = 90
c = 333.1γ = 90
Software Package:
Software NamePurpose
PHASERphasing
BUSTERrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
Aimlessdata scaling

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 2.0: 2020-10-07
    Changes: Atomic model, Data collection, Derived calculations, Non-polymer description, Structure summary
  • Version 2.1: 2024-01-10
    Changes: Data collection, Database references, Refinement description