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The transcription factor STAT5 catalyzes Mannich ligation reactions yielding inhibitors of leukemic cell proliferation
Protein-templated fragment ligations have been established as a powerful method for the assembly and detection of optimized protein ligands. Initially developed for reversible ligations, the method has been expanded to irreversible reactions enabling the formation of super-additive fragment combinat...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325109/ https://www.ncbi.nlm.nih.gov/pubmed/30622248 http://dx.doi.org/10.1038/s41467-018-07923-2 |
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author | Wong, Ee Lin Nawrotzky, Eric Arkona, Christoph Kim, Boo Geun Beligny, Samuel Wang, Xinning Wagner, Stefan Lisurek, Michael Carstanjen, Dirk Rademann, Jörg |
author_facet | Wong, Ee Lin Nawrotzky, Eric Arkona, Christoph Kim, Boo Geun Beligny, Samuel Wang, Xinning Wagner, Stefan Lisurek, Michael Carstanjen, Dirk Rademann, Jörg |
author_sort | Wong, Ee Lin |
collection | PubMed |
description | Protein-templated fragment ligations have been established as a powerful method for the assembly and detection of optimized protein ligands. Initially developed for reversible ligations, the method has been expanded to irreversible reactions enabling the formation of super-additive fragment combinations. Here, protein-induced Mannich ligations are discovered as a biocatalytic reaction furnishing inhibitors of the transcription factor STAT5. STAT5 protein catalyzes multicomponent reactions of a phosphate mimetic, formaldehyde, and 1H-tetrazoles yielding protein ligands with greatly increased binding affinity and ligand efficiency. Reactions are induced under physiological conditions selectively by native STAT5 but not by other proteins. Formation of ligation products and (auto-)inhibition of the reaction are quantified and the mechanism is investigated. Inhibitors assembled by STAT5 block specifically the phosphorylation of this protein in a cellular model of acute myeloid leukemia (AML), DNA-binding of STAT5 dimers, expression of downstream targets of the transcription factor, and the proliferation of cancer cells in mice. |
format | Online Article Text |
id | pubmed-6325109 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-63251092019-01-10 The transcription factor STAT5 catalyzes Mannich ligation reactions yielding inhibitors of leukemic cell proliferation Wong, Ee Lin Nawrotzky, Eric Arkona, Christoph Kim, Boo Geun Beligny, Samuel Wang, Xinning Wagner, Stefan Lisurek, Michael Carstanjen, Dirk Rademann, Jörg Nat Commun Article Protein-templated fragment ligations have been established as a powerful method for the assembly and detection of optimized protein ligands. Initially developed for reversible ligations, the method has been expanded to irreversible reactions enabling the formation of super-additive fragment combinations. Here, protein-induced Mannich ligations are discovered as a biocatalytic reaction furnishing inhibitors of the transcription factor STAT5. STAT5 protein catalyzes multicomponent reactions of a phosphate mimetic, formaldehyde, and 1H-tetrazoles yielding protein ligands with greatly increased binding affinity and ligand efficiency. Reactions are induced under physiological conditions selectively by native STAT5 but not by other proteins. Formation of ligation products and (auto-)inhibition of the reaction are quantified and the mechanism is investigated. Inhibitors assembled by STAT5 block specifically the phosphorylation of this protein in a cellular model of acute myeloid leukemia (AML), DNA-binding of STAT5 dimers, expression of downstream targets of the transcription factor, and the proliferation of cancer cells in mice. Nature Publishing Group UK 2019-01-08 /pmc/articles/PMC6325109/ /pubmed/30622248 http://dx.doi.org/10.1038/s41467-018-07923-2 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Wong, Ee Lin Nawrotzky, Eric Arkona, Christoph Kim, Boo Geun Beligny, Samuel Wang, Xinning Wagner, Stefan Lisurek, Michael Carstanjen, Dirk Rademann, Jörg The transcription factor STAT5 catalyzes Mannich ligation reactions yielding inhibitors of leukemic cell proliferation |
title | The transcription factor STAT5 catalyzes Mannich ligation reactions yielding inhibitors of leukemic cell proliferation |
title_full | The transcription factor STAT5 catalyzes Mannich ligation reactions yielding inhibitors of leukemic cell proliferation |
title_fullStr | The transcription factor STAT5 catalyzes Mannich ligation reactions yielding inhibitors of leukemic cell proliferation |
title_full_unstemmed | The transcription factor STAT5 catalyzes Mannich ligation reactions yielding inhibitors of leukemic cell proliferation |
title_short | The transcription factor STAT5 catalyzes Mannich ligation reactions yielding inhibitors of leukemic cell proliferation |
title_sort | transcription factor stat5 catalyzes mannich ligation reactions yielding inhibitors of leukemic cell proliferation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325109/ https://www.ncbi.nlm.nih.gov/pubmed/30622248 http://dx.doi.org/10.1038/s41467-018-07923-2 |
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