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Structural basis and selectivity of tankyrase inhibition by a Wnt signaling inhibitor WIKI4.

ABSTRACT: Recently a novel inhibitor of Wnt signaling was discovered. The compound, WIKI4, was found to act through tankyrase inhibition and regulate ?-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.

SUBMITTER: Haikarainen T

PROVIDER: S-EPMC3675114 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Structural basis and selectivity of tankyrase inhibition by a Wnt signaling inhibitor WIKI4.

Haikarainen Teemu T Venkannagari Harikanth H Narwal Mohit M Obaji Ezeogo E Lee Hao-Wei HW Nkizinkiko Yves Y Lehtiö Lari L

PloS one 20130606 6

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 no ...[more]

PMID: 23762361

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