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

20 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Tankyrases
embryonic stem cells
adenosine
active sites
X-ray diffraction
cell lines
enzymes
proteins
Catenins
X ray crystallography
X Ray Crystallography
Stem cells
Scaffolds
NAD
Adenosine
Catalytic Domain
Cells
neoplasm cells
Cell Line
Enzymes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

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

Structural Basis and Selectivity of Tankyrase Inhibition by a Wnt Signaling Inhibitor WIKI4. / Haikarainen, Teemu; Venkannagari, Harikanth; Narwal, Mohit; Obaji, Ezeogo; Lee, Hao Wei; Nkizinkiko, Yves; Lehtiö, Lari.

In: PLoS One, Vol. 8, No. 6, e65404, 06.06.2013.

Research output: Contribution to journalArticle

Haikarainen, T, Venkannagari, H, Narwal, M, Obaji, E, Lee, HW, Nkizinkiko, Y & Lehtiö, L 2013, 'Structural Basis and Selectivity of Tankyrase Inhibition by a Wnt Signaling Inhibitor WIKI4', PLoS One, vol. 8, no. 6, e65404. https://doi.org/10.1371/journal.pone.0065404
Haikarainen, Teemu ; Venkannagari, Harikanth ; Narwal, Mohit ; Obaji, Ezeogo ; Lee, Hao Wei ; Nkizinkiko, Yves ; Lehtiö, Lari. / Structural Basis and Selectivity of Tankyrase Inhibition by a Wnt Signaling Inhibitor WIKI4. In: PLoS One. 2013 ; Vol. 8, No. 6.
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