Abstract
Tankyrases (TNKS1 and TNKS2) are key regulators of cellular processes such as telomere pathway and Wnt signaling. IWRs (inhibitors of Wnt response) have recently been identified as potent and selective inhibitors of tankyrases. However, it is not clear how these IWRs interact with tankyrases. Here we report the crystal structure of the catalytic domain of human TNKS1 in complex with IWR2, which reveals a novel binding site for tankyrase inhibitors. The TNKS1/IWR2 complex provides a molecular basis for their strong and specific interactions and suggests clues for further development of tankyrase inhibitors.
Highlights
The two highly homologous human tankyrase isoforms, TNKS1 and TNKS2, are members of the poly ADP-ribose polymerase (PARP) family of 17 proteins that share a catalytic PARP domain [1]
Structural studies of PARP inhibitor complexes reveal that these compounds are anchored in the nicotinamide pocket in a very similar manner [4]
XAV939 binds to the nicotinamide pocket of TNKS2 through interactions similar to those observed in other PARP inhibitor complexes (Figure 1) [8], maintaining the three aforementioned, conserved hydrogen bonds with a serine hydroxyl, as well as the oxygen and NH from a glycine main chain
Summary
The two highly homologous human tankyrase isoforms, TNKS1 and TNKS2, are members of the poly ADP-ribose polymerase (PARP) family of 17 proteins that share a catalytic PARP domain [1]. Structural studies of PARP inhibitor complexes reveal that these compounds are anchored in the nicotinamide pocket in a very similar manner [4].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
