Structural Basis and Selectivity of Tankyrase Inhibition by a Wnt Signaling Inhibitor WIKI4

Teemu Haikarainen, Harikanth Venkannagari, Mohit Narwal, Ezeogo Obaji, Hao Wei Lee, Yves Nkizinkiko, Lari Lehtiö

Research output: Contribution to journalArticle

21 Scopus citations

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 languageEnglish (US)
Article numbere65404
JournalPloS one
Volume8
Issue number6
DOIs
StatePublished - 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