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Human Tankyrase-2, catalytic PARP domain in complex with the potent inhibitor XAV939

PDB Code 3KR8 Target Class Poly ADP-ribose polymerase Target Tankyrase-2 + XAV939 Alias PARP-5b, PARP-5c, PARP5B, PARP5C, TANK2, TNKL, TNKS2 Disease Area/Function cancer Date Deposited Nov 18 2009 Authors T.KARLBERG, P.SCHUTZ, C.H.ARROWSMITH, H.BERGLUND, C.BOUNTRA, R.COLLINS, A.M.EDWARDS, S.FLODIN, A.FLORES, S.GRASLUND, M.HAMMARSTROM, A.JOHANSSON, I.JOHANSSON, A.KALLAS, T.KOTENYOVA, A.KOTZSCH, P.KRAULIS, T.K.NIELSEN, M.MOCHE, P.NORDLUND, T.NYMAN, C.PERSSON, M.I.SIPONEN, A.G.THORSELL, L.TRESAUGUES, S.VAN DEN BERG, J.WEIGELT, M.WELIN, M.WISNIEWSKA, H.SCHULER Related Structure 3KR7, 3MHK, 3MHJ

About this structure

Tankyrases are poly-ADP-ribose transferases, owing to their C-terminal PARP-homology domain (1-5). Tankyrases are positive regulators of telomere elongation; they poly-ADP-ribosylate and displace TRF1 from telomeric repeats thereby allowing telomerase access to telomere ends (1,5). Tankyrases also mark the β-catenin destruction complex component axin for degradation, and tankyrase inhibition antagonizes the Wnt signal transduction pathway by stimulating β-catenin degradation (6). Inhibition of tankyrase activity imposes selective lethality on BRCA deficient cell lines (7). Thus, inhibition of tankyrase activity is a promising strategy for targeting cancer by diverse mechanisms.

Here we present the crystal structure of the human tankyrase-2 PARP domain in complex with its potent inhibitor XAV939 (6) at 2.1 Å. The structure was obtained after soaking apo crystals (pdb entry 3KR7) with the compound. The complex structure shows binding of the ligand to the nicotinamide pocket as in other PARP ligand complexes, but additional specific contacts are of mainly non-polar nature.

References

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  2. Kaminker PG et al. (2001) TANK2, a new TRF1-associated poly(ADP-ribose) polymerase, causes rapid induction of cell death upon overexpression. J. Biol. Chem. 276, 35891-35899. PubMed 11454873
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  7. McCabe N et al. (2009) Targeting Tankyrase 1 as a therapeutic strategy for BRCA-associated cancer. Oncogene 28, 1465-1470. PubMed 19182824