Structure of Human Tankyrase-1 in Complex with Small Molecule Inhibitors, PJ34 and XAV939

Here we report the crystal structure of Tankyrase-1 (TNKS1) in complex with two small molecule inhibitors, PJ34 and XAV939, both to 2.0Å resolution. The structure of the TNKS1 in complex with PJ34 reveals two molecules of PJ34 bound into the NAD+ donor pocket. One molecule is in the nicotinamide portion of the pocket, as previously observed in other PARP structures, while the second molecule is bound in the adenosine portion of the groove. Additionally, unlike the unliganded crystallization system, the TNKS1/PJ34 crystallization system has the NAD+ donor site accessible to bulk solvent in the crystal which allows for displacement soaking. . This TNKS1/PJ34 crystallization system was used to determine the structure of TNKS1 in complex with XAV939. These structures provide a basis for the start of a structure based drug design campaign for TNKS1