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:	Teemu Haikarainen, Harikanth Venkannagari, Mohit Narwal, Ezeogo Obaji, Hao-Wei Lee, Yves Nkizinkiko, Lari Lehtiö
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d65d152848a14c07afbd50647aa37410
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spelling	oai:doaj.org-article:d65d152848a14c07afbd50647aa374102021-11-18T07:42:45ZStructural basis and selectivity of tankyrase inhibition by a Wnt signaling inhibitor WIKI4.1932-620310.1371/journal.pone.0065404https://doaj.org/article/d65d152848a14c07afbd50647aa374102013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23762361/?tool=EBIhttps://doaj.org/toc/1932-6203Recently 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.Teemu HaikarainenHarikanth VenkannagariMohit NarwalEzeogo ObajiHao-Wei LeeYves NkizinkikoLari LehtiöPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 6, p e65404 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Teemu Haikarainen Harikanth Venkannagari Mohit Narwal Ezeogo Obaji Hao-Wei Lee Yves Nkizinkiko Lari Lehtiö Structural basis and selectivity of tankyrase inhibition by a Wnt signaling inhibitor WIKI4.
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.
format	article
author	Teemu Haikarainen Harikanth Venkannagari Mohit Narwal Ezeogo Obaji Hao-Wei Lee Yves Nkizinkiko Lari Lehtiö
author_facet	Teemu Haikarainen Harikanth Venkannagari Mohit Narwal Ezeogo Obaji Hao-Wei Lee Yves Nkizinkiko Lari Lehtiö
author_sort	Teemu Haikarainen
title	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_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_sort	structural basis and selectivity of tankyrase inhibition by a wnt signaling inhibitor wiki4.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/d65d152848a14c07afbd50647aa37410
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Structural basis and selectivity of tankyrase inhibition by a Wnt signaling inhibitor WIKI4.

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