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

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 selectiv...

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Autores principales: Haikarainen, Teemu, Venkannagari, Harikanth, Narwal, Mohit, Obaji, Ezeogo, Lee, Hao-Wei, Nkizinkiko, Yves, Lehtiö, Lari
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3675114/
https://www.ncbi.nlm.nih.gov/pubmed/23762361
http://dx.doi.org/10.1371/journal.pone.0065404
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author Haikarainen, Teemu
Venkannagari, Harikanth
Narwal, Mohit
Obaji, Ezeogo
Lee, Hao-Wei
Nkizinkiko, Yves
Lehtiö, Lari
author_facet Haikarainen, Teemu
Venkannagari, Harikanth
Narwal, Mohit
Obaji, Ezeogo
Lee, Hao-Wei
Nkizinkiko, Yves
Lehtiö, Lari
author_sort Haikarainen, Teemu
collection PubMed
description 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.
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spelling pubmed-36751142013-06-12 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 PLoS One Research Article 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. Public Library of Science 2013-06-06 /pmc/articles/PMC3675114/ /pubmed/23762361 http://dx.doi.org/10.1371/journal.pone.0065404 Text en © 2013 Haikarainen et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
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
title Structural Basis and Selectivity of Tankyrase Inhibition by a Wnt Signaling Inhibitor WIKI4
title_full Structural Basis and Selectivity of Tankyrase Inhibition by a Wnt Signaling Inhibitor WIKI4
title_fullStr Structural Basis and Selectivity of Tankyrase Inhibition by a Wnt Signaling Inhibitor WIKI4
title_full_unstemmed Structural Basis and Selectivity of Tankyrase Inhibition by a Wnt Signaling Inhibitor WIKI4
title_short Structural Basis and Selectivity of Tankyrase Inhibition by a Wnt Signaling Inhibitor WIKI4
title_sort structural basis and selectivity of tankyrase inhibition by a wnt signaling inhibitor wiki4
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3675114/
https://www.ncbi.nlm.nih.gov/pubmed/23762361
http://dx.doi.org/10.1371/journal.pone.0065404
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