4L34

Tankyrase 2 in complex with 4'-tetrazole flavone


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.202 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.172 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of tankyrase inhibiting flavones with increased potency and isoenzyme selectivity.

Narwal, M.Koivunen, J.Haikarainen, T.Obaji, E.Legala, O.E.Venkannagari, H.Joensuu, P.Pihlajaniemi, T.Lehtio, L.

(2013) J Med Chem 56: 7880-7889

  • DOI: https://doi.org/10.1021/jm401463y
  • Primary Citation of Related Structures:  
    4BS4, 4KZL, 4KZQ, 4KZU, 4L09, 4L0B, 4L0I, 4L0S, 4L0T, 4L0V, 4L10, 4L2F, 4L2G, 4L2K, 4L31, 4L32, 4L33, 4L34

  • PubMed Abstract: 

    Tankyrases are ADP-ribosyltransferases that play key roles in various cellular pathways, including the regulation of cell proliferation, and thus, they are promising drug targets for the treatment of cancer. Flavones have been shown to inhibit tankyrases and we report here the discovery of more potent and selective flavone derivatives. Commercially available flavones with single substitutions were used for structure-activity relationship studies, and cocrystal structures of the 18 hit compounds were analyzed to explain their potency and selectivity. The most potent inhibitors were also tested in a cell-based assay, which demonstrated that they effectively antagonize Wnt signaling. To assess selectivity, they were further tested against a panel of homologous human ADP-ribosyltransferases. The most effective compound, 22 (MN-64), showed 6 nM potency against tankyrase 1, isoenzyme selectivity, and Wnt signaling inhibition. This work forms a basis for rational development of flavones as tankyrase inhibitors and guides the development of other structurally related inhibitors.


  • Organizational Affiliation

    Department of Biochemistry and Biocenter Oulu, University of Oulu , Oulu 90570, Finland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tankyrase-2A,
C [auth B]
191Homo sapiensMutation(s): 0 
Gene Names: TNKS2PARP5BTANK2TNKL
EC: 2.4.2.30
UniProt & NIH Common Fund Data Resources
Find proteins for Q9H2K2 (Homo sapiens)
Explore Q9H2K2 
Go to UniProtKB:  Q9H2K2
PHAROS:  Q9H2K2
GTEx:  ENSG00000107854 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9H2K2
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Tankyrase-2B [auth C],
D
49Homo sapiensMutation(s): 0 
Gene Names: TNKS2PARP5BTANK2TNKL
EC: 2.4.2.30
UniProt & NIH Common Fund Data Resources
Find proteins for Q9H2K2 (Homo sapiens)
Explore Q9H2K2 
Go to UniProtKB:  Q9H2K2
PHAROS:  Q9H2K2
GTEx:  ENSG00000107854 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9H2K2
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1VG
Query on 1VG

Download Ideal Coordinates CCD File 
H [auth A],
M [auth B]
2-[4-(1H-tetrazol-5-yl)phenyl]-4H-chromen-4-one
C16 H10 N4 O2
CDSSKRNFCDQPBZ-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
F [auth A],
G [auth A],
K [auth B],
L [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

Download Ideal Coordinates CCD File 
I [auth C]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
E [auth A],
J [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1VG PDBBind:  4L34 IC50: 114 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.202 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.172 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 91.78α = 90
b = 97.67β = 90
c = 117.42γ = 90
Software Package:
Software NamePurpose
MxCuBEdata collection
MOLREPphasing
REFMACrefinement
XDSdata reduction
XSCALEdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-10-30
    Type: Initial release
  • Version 1.1: 2014-01-15
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description