7ZY2

Crystal structure of compound 7 bound to CK2alpha


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.51 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.189 

Starting Model: experimental
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This is version 1.2 of the entry. See complete history


Literature

A fragment-based approach leading to the discovery of inhibitors of CK2 alpha with a novel mechanism of action.

Brear, P.De Fusco, C.Atkinson, E.L.Iegre, J.Francis-Newton, N.J.Venkitaraman, A.R.Hyvonen, M.Spring, D.R.

(2022) RSC Med Chem 13: 1420-1426

  • DOI: https://doi.org/10.1039/d2md00161f
  • Primary Citation of Related Structures:  
    7ZY0, 7ZY2, 7ZY5, 7ZY8, 7ZYD, 7ZYK, 7ZYO, 7ZYR, 8AE7, 8AEC, 8AEK, 8AEM

  • PubMed Abstract: 

    CK2 is a ubiquitous protein kinase with an anti-apoptotic role and is found to be overexpressed in multiple cancer types. To this end, the inhibition of CK2 is of great interest with regard to the development of novel anti-cancer therapeutics. ATP-site inhibition of CK2 is possible; however, this typically results in poor selectivity due to the highly conserved nature of the catalytic site amongst kinases. An alternative methodology for the modulation of CK2 activity is through allosteric inhibition. The recently identified αD site represents a promising binding site for allosteric inhibition of CK2α. The work presented herein describes the development of a series of CK2α allosteric inhibitors through iterative cycles of X-ray crystallography and enzymatic assays, in addition to both fragment growing and fragment merging design strategies. The lead fragment developed, fragment 8, exhibits a high ligand efficiency, displays no drop off in activity between enzymatic and cellular assays, and successfully engages CK2α in cells. Furthermore, X-ray crystallographic analysis provided indications towards a novel mechanism of allosteric inhibition through αD site binding. Fragments described in this paper therefore represent promising starting points for the development of highly selective allosteric CK2 inhibitors.


  • Organizational Affiliation

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


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Casein kinase II subunit alpha328Homo sapiensMutation(s): 4 
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
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.51 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.189 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.782α = 90
b = 45.916β = 111.88
c = 63.286γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
Aimlessdata scaling
PDB_EXTRACTdata extraction
XDSdata reduction
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Wellcome TrustUnited Kingdom107714/Z/15/Z
Wellcome TrustUnited Kingdom090340/Z/09/Z

Revision History  (Full details and data files)

  • Version 1.0: 2022-10-12
    Type: Initial release
  • Version 1.1: 2023-03-29
    Changes: Database references
  • Version 1.2: 2024-02-07
    Changes: Data collection, Refinement description