Figure 1.
Structure of TNKS2 ARTD domain.
Acceptor and donor NAD+ binding sites, including nicotinamide subsite (NI) and adenosine subsite (ADE) are labelled.
Table 1.
Conditions used for the profiling of the inhibitors against human ARTDs.
Table 2.
Data collection and refinement statistics.
Figure 2.
Potency of WIKI4 against TNKS1.
The in vitro dose response curves were measured three times with a fluorescence-based homogenous activity assay.
Figure 3.
Profiling of inhibitor selectivity.
The selectivity of WIKI4 against 8 ARTDs polymerases was measured at 10 µM concentration. XAV939 and IWR-1 were used as controls.
Figure 4.
a) An overview of TNKS2 structure showing the binding site of WIKI4 (lilac) and XAV939 (dark purple) (pdb accession code 3KR8). b) Comparison of apo TNKS2 structure (pink) (pdb accession code 3KR7) and WIKI4 (turquoise) bound structure of TNKS2. c) Surface electrostatic presentation of WIKI4 binding site. Positive (surface potential charge above 0.25 V) and negative (surface potential charge below −0.25 V) electrostatic regions are colored blue and red, respectively.
Figure 5.
Interactions of WIKI4 with TNKS2 catalytic domain.
a) Chemical structure of WIKI4. b) Binding mode of WIKI4 to monomer A. c) Binding mode of WIKI4 to monomer B.
Figure 6.
Comparison of WIKI4 binding to tankyrase 2 with other tankyrase selective inhibitors and with ARTD1-3 structures.
WIKI4 - TNKS2 protein structure is colored in turquoise and WIKI4 is colored in lilac. a) Comparison of the WIKI4 binding sites in TNKS2, ARTD1 (pink) (pdb accession code 3GJW), ARTD2 (green) (pdb accession code 3KCZ), and ARTD3 (red) (pdb accession code 3FHB). ARD, ARTD regulatory domain. b) Comparison of the binding of WIKI4 and IWR-1. Hydrogen bonds for WIKI4 and IWR-1 are shown in black and gray dotted lines, respectively. IWR-1 - TNKS2 protein structure is colored in pink and IWR-1 is colored in orange. c) Comparison of the binding of WIKI4 and G007-LK. Hydrogen bonds for WIKI4 and G007-LK are shown in black and gray dotted lines, respectively. G007-LK - TNKS2 protein structure is colored in pink and G007-LK is colored in orange.