5ADQ

Crystal structure of human tankyrase 2 in complex with JW55


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.190 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Development and Structural Analysis of Adenosine Site Binding Tankyrase Inhibitors.

Haikarainen, T.Waaler, J.Ignatev, A.Nkizinkiko, Y.Venkannagari, H.Obaji, E.Krauss, S.Lehtio, L.

(2016) Bioorg Med Chem Lett 26: 328

  • DOI: https://doi.org/10.1016/j.bmcl.2015.12.018
  • Primary Citation of Related Structures:  
    5ADQ, 5ADR, 5ADS, 5ADT, 5AEH

  • PubMed Abstract: 

    Tankyrases 1 and 2, the specialized members of the ARTD protein family, are druggable biotargets whose inhibition may have therapeutic potential against cancer, metabolic disease, fibrotic disease, fibrotic wound healing and HSV viral infections. We have previously identified a novel tankyrase inhibitor scaffold, JW55, and showed that it reduces mouse colon adenoma formation in vivo. Here we expanded the scaffold and profiled the selectivity of the compounds against a panel of human ARTDs. The scaffold also enables a fine modulation of selectivity towards either tankyrase 1 or tankyrase 2. In order to get insight about the binding mode of the inhibitors, we solved crystal structures of the compounds in complex with tankyrase 2. The compounds bind to the adenosine pocket of the catalytic domain and cause changes in the protein structure that are modulated by the chemical modifications of the compounds. The structural analysis allows further rational development of this compound class as a potent and selective tankyrase inhibitor.


  • Organizational Affiliation

    Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
TANKYRASE-2191Homo sapiensMutation(s): 0 
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
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
TANKYRASE-248Homo sapiensMutation(s): 0 
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 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
A95
Query on A95

Download Ideal Coordinates CCD File 
F [auth A]N-(4-(((4-(4-methoxyphenyl)oxan-4- yl)methyl)carbamoyl)phenyl)furan-2-carboxamide
C25 H26 N2 O5
ZJZWZIXSGNFWQQ-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

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

Download Ideal Coordinates CCD File 
C [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
BCT
Query on BCT

Download Ideal Coordinates CCD File 
G [auth A]BICARBONATE ION
C H O3
BVKZGUZCCUSVTD-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
A95 BindingDB:  5ADQ IC50: min: 1800, max: 2010 (nM) from 4 assay(s)
Binding MOAD:  5ADQ IC50: 2010 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.190 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 66.17α = 90
b = 66.17β = 90
c = 121.61γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-01-13
    Type: Initial release
  • Version 1.1: 2016-01-20
    Changes: Database references
  • Version 1.2: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description