4TJY

Crystal Structure of human Tankyrase 2 in complex with ABT-888.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.178 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Insights into the binding of PARP inhibitors to the catalytic domain of human tankyrase-2.

Qiu, W.Lam, R.Voytyuk, O.Romanov, V.Gordon, R.Gebremeskel, S.Vodsedalek, J.Thompson, C.Beletskaya, I.Battaile, K.P.Pai, E.F.Rottapel, R.Chirgadze, N.Y.

(2014) Acta Crystallogr D Biol Crystallogr 70: 2740-2753

  • DOI: https://doi.org/10.1107/S1399004714017660
  • Primary Citation of Related Structures:  
    4PML, 4PNL, 4PNM, 4PNN, 4PNQ, 4PNR, 4PNS, 4PNT, 4TJU, 4TJW, 4TJY, 4TK0, 4TK5, 4TKF, 4TKG, 4TKI

  • PubMed Abstract: 

    The poly(ADP-ribose) polymerase (PARP) family represents a new class of therapeutic targets with diverse potential disease indications. PARP1 and PARP2 inhibitors have been developed for breast and ovarian tumors manifesting double-stranded DNA-repair defects, whereas tankyrase 1 and 2 (TNKS1 and TNKS2, also known as PARP5a and PARP5b, respectively) inhibitors have been developed for tumors with elevated β-catenin activity. As the clinical relevance of PARP inhibitors continues to be actively explored, there is heightened interest in the design of selective inhibitors based on the detailed structural features of how small-molecule inhibitors bind to each of the PARP family members. Here, the high-resolution crystal structures of the human TNKS2 PARP domain in complex with 16 various PARP inhibitors are reported, including the compounds BSI-201, AZD-2281 and ABT-888, which are currently in Phase 2 or 3 clinical trials. These structures provide insight into the inhibitor-binding modes for the tankyrase PARP domain and valuable information to guide the rational design of future tankyrase-specific inhibitors.


  • Organizational Affiliation

    Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tankyrase-2
A, B, C, D
227Homo 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
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.178 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.11α = 90
b = 79.57β = 90
c = 153.78γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction
BUSTERrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-10-15
    Type: Initial release
  • Version 1.1: 2015-01-07
    Changes: Database references
  • Version 1.2: 2015-02-04
    Changes: Derived calculations
  • Version 1.3: 2023-12-27
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description, Source and taxonomy, Structure summary