Abstract
Recently a novel inhibitor of Wnt signaling was discovered. The compound, WIKI4, was found to act through tankyrase inhibition and regulate β-catenin levels in many cancer cell lines and human embryonic stem cells. Here we confirm that WIKI4 is a high potency tankyrase inhibitor and that it selectively inhibits tankyrases over other ARTD enzymes tested. The binding mode of the compound to tankyrase 2 was determined by protein X-ray crystallography to 2.4 Å resolution. The structure revealed a novel binding mode to the adenosine subsite of the donor NAD+ binding groove of the catalytic domain. Our results form a structural basis for further development of potent and selective tankyrase inhibitors based on the WIKI4 scaffold.
| Original language | English (US) |
|---|---|
| Article number | e65404 |
| Journal | PloS one |
| Volume | 8 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 6 2013 |
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Agricultural and Biological Sciences(all)
- General
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Haikarainen, T., Venkannagari, H., Narwal, M., Obaji, E., Lee, H. W., Nkizinkiko, Y., & Lehtiö, L. (2013). Structural Basis and Selectivity of Tankyrase Inhibition by a Wnt Signaling Inhibitor WIKI4. PloS one, 8(6), [e65404]. https://doi.org/10.1371/journal.pone.0065404