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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| Veröffentlicht in: | PloS one 2013-06, Vol.8 (6), p.e65404-e65404 |
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| creator | Haikarainen, Teemu Venkannagari, Harikanth Narwal, Mohit Obaji, Ezeogo Lee, Hao-Wei Nkizinkiko, Yves Lehtiö, Lari |
| 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. |
| doi_str_mv | 10.1371/journal.pone.0065404 |
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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. 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This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Haikarainen et al 2013 Haikarainen et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-9ba887355f8f5450cfbe42ca02b867b65e45e1d634c838408e1c1cdeca31ca583</citedby><cites>FETCH-LOGICAL-c758t-9ba887355f8f5450cfbe42ca02b867b65e45e1d634c838408e1c1cdeca31ca583</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3675114/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3675114/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2100,2926,23864,27922,27923,53789,53791,79370,79371</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23762361$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Seifert, Roland</contributor><creatorcontrib>Haikarainen, Teemu</creatorcontrib><creatorcontrib>Venkannagari, Harikanth</creatorcontrib><creatorcontrib>Narwal, Mohit</creatorcontrib><creatorcontrib>Obaji, Ezeogo</creatorcontrib><creatorcontrib>Lee, Hao-Wei</creatorcontrib><creatorcontrib>Nkizinkiko, Yves</creatorcontrib><creatorcontrib>Lehtiö, Lari</creatorcontrib><title>Structural basis and selectivity of tankyrase inhibition by a Wnt signaling inhibitor WIKI4</title><title>PloS one</title><addtitle>PLoS One</addtitle><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. 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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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23762361</pmid><doi>10.1371/journal.pone.0065404</doi><tpages>e65404</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adenosine Amino Acid Sequence Antineoplastic Agents - chemistry Binding Biochemistry Biology Cancer Catalysis Catalytic Domain Cell Line, Tumor Cloning Crystal structure Crystallography Crystallography, X-Ray DNA damage Embryo cells Embryonic stem cells Enzyme Inhibitors Enzymes Humans Inhibition Inhibitors Kinases Materials Science Medicine Molecular Docking Simulation Molecular Sequence Data NAD NAD - chemistry Naphthalimides - chemistry Pharmaceutical sciences Protein Binding Proteins Recombinant Proteins - chemistry Recombinant Proteins - genetics Selectivity Senescence Sensitivity and Specificity Signaling Stem cells Tankyrases - antagonists & inhibitors Tankyrases - chemistry Tankyrases - genetics Telomerase Triazoles - chemistry Tumor cell lines Wnt protein Wnt Signaling Pathway X-ray crystallography β-Catenin |
| title | Structural basis and selectivity of tankyrase inhibition by a Wnt signaling inhibitor WIKI4 |
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