5OKT

Crystal structure of human Casein Kinase I delta in complex with IWP-2

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.13 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.194 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history. 


Literature

Discovery of Inhibitor of Wnt Production 2 (IWP-2) and Related Compounds As Selective ATP-Competitive Inhibitors of Casein Kinase 1 (CK1) delta / epsilon.

Garcia-Reyes, B., Witt, L., Jansen, B., Karasu, E., Gehring, T., Leban, J., Henne-Bruns, D., Pichlo, C., Brunstein, E., Baumann, U., Wesseler, F., Rathmer, B., Schade, D., Peifer, C., Knippschild, U.

(2018) J Med Chem 61: 4087-4102

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b00095
  • Primary Citation of Related Structures:  
    5OKT

  • PubMed Abstract: 

    Inhibitors of Wnt production (IWPs) are known antagonists of the Wnt pathway, targeting the membrane-bound O-acyltransferase porcupine (Porcn) and thus preventing a crucial Wnt ligand palmitoylation. Since IWPs show structural similarities to benzimidazole-based CK1 inhibitors, we hypothesized that IWPs could also inhibit CK1 isoforms. Molecular modeling revealed a plausible binding mode of IWP-2 in the ATP binding pocket of CK1δ which was confirmed by X-ray analysis. In vitro kinase assays demonstrated IWPs to be ATP-competitive inhibitors of wt CK1δ. IWPs also strongly inhibited the gatekeeper mutant M82F CK1δ. When profiled in a panel of 320 kinases, IWP-2 specifically inhibited CK1δ. IWP-2 and IWP-4 also inhibited the viability of various cancer cell lines. By a medicinal chemistry approach, we developed improved IWP-derived CK1 inhibitors. Our results suggest that the effects of IWPs are not limited to Porcn, but also might influence CK1δ/ε-related pathways.

    • Organizational Affiliation: 

    Department of General and Visceral Surgery , Ulm University Hospital , Albert-Einstein-Allee 23 , D-89081 Ulm , Germany.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Casein kinase I isoform delta
A, B
314Homo sapiensMutation(s): 0 
Gene Names: CSNK1D, HCKID
EC: 2.7.11.1 (PDB Primary Data), 2.7.11.26 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P48730 (Homo sapiens)
Explore P48730 
Go to UniProtKB:  P48730
PHAROS:  P48730
GTEx:  ENSG00000141551 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP48730
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Casein kinase I isoform delta
C, D
314Homo sapiensMutation(s): 0 
Gene Names: CSNK1D, HCKID
EC: 2.7.11.1 (PDB Primary Data), 2.7.11.26 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P48730 (Homo sapiens)
Explore P48730 
Go to UniProtKB:  P48730
PHAROS:  P48730
GTEx:  ENSG00000141551 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP48730
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
9XK
Query on 9XK
Download Ideal Coordinates CCD File 
AA [auth D],
E [auth A],
M [auth B],
R [auth C]		~{N}-(6-methyl-1,3-benzothiazol-2-yl)-2-[(4-oxidanylidene-3-phenyl-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)sulfanyl]ethanamide
C22 H18 N4 O2 S3
WRKPZSMRWPJJDH-UHFFFAOYSA-N
SO4
Query on SO4
Download Ideal Coordinates CCD File 
BA [auth D]
CA [auth D]
DA [auth D]
EA [auth D]
F [auth A]
BA [auth D],
CA [auth D],
DA [auth D],
EA [auth D],
F [auth A],
FA [auth D],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
N [auth B],
O [auth B],
P [auth B],
S [auth C],
T [auth C],
U [auth C],
V [auth C],
W [auth C],
X [auth C]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL
Download Ideal Coordinates CCD File 
GA [auth D],
Q [auth B],
Y [auth C],
Z [auth C]		GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ACT
Query on ACT
Download Ideal Coordinates CCD File 
K [auth A],
L [auth A]		ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
TPO
Query on TPO
A, B
L-PEPTIDE LINKINGC4 H10 N O6 PTHR
Binding Affinity Annotations 
IDSourceBinding Affinity
9XK BindingDB:  5OKT IC50: min: 40, max: 4030 (nM) from 4 assay(s)
Binding MOAD:  5OKT IC50: 317 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.13 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.194 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 49.11α = 89.73
b = 82.73β = 74.14
c = 89.64γ = 86.57
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XSCALEdata scaling
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-04-25
    Type: Initial release
  • Version 1.1: 2018-05-23
    Changes: Data collection, Database references
  • Version 1.2: 2019-10-16
    Changes: Data collection
  • Version 1.3: 2024-01-17
    Changes: Advisory, Data collection, Database references, Refinement description