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 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Agricultural and Biological Sciences(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Medicine(all)
Cite this
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 journal › Article
}
TY - JOUR
T1 - Structural Basis and Selectivity of Tankyrase Inhibition by a Wnt Signaling Inhibitor WIKI4
AU - Haikarainen, Teemu
AU - Venkannagari, Harikanth
AU - Narwal, Mohit
AU - Obaji, Ezeogo
AU - Lee, Hao Wei
AU - Nkizinkiko, Yves
AU - Lehtiö, Lari
PY - 2013/6/6
Y1 - 2013/6/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84878798918&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84878798918&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0065404
DO - 10.1371/journal.pone.0065404
M3 - Article
VL - 8
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 6
M1 - e65404
ER -