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Structural basis for the activation and inhibition of Sirtuin 6 by quercetin and its derivatives
Mammalian Sirtuin 6 (Sirt6) is an NAD(+)-dependent protein deacylase regulating metabolism and chromatin homeostasis. Sirt6 activation protects against metabolic and aging-related diseases, and Sirt6 inhibition is considered a cancer therapy. Available Sirt6 modulators show insufficient potency and...
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/PMC6914789/ https://www.ncbi.nlm.nih.gov/pubmed/31844103 http://dx.doi.org/10.1038/s41598-019-55654-1 |
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author | You, Weijie Zheng, Wei Weiss, Sandra Chua, Katrin F. Steegborn, Clemens |
author_facet | You, Weijie Zheng, Wei Weiss, Sandra Chua, Katrin F. Steegborn, Clemens |
author_sort | You, Weijie |
collection | PubMed |
description | Mammalian Sirtuin 6 (Sirt6) is an NAD(+)-dependent protein deacylase regulating metabolism and chromatin homeostasis. Sirt6 activation protects against metabolic and aging-related diseases, and Sirt6 inhibition is considered a cancer therapy. Available Sirt6 modulators show insufficient potency and specificity, and even partially contradictory Sirt6 effects were reported for the plant flavone quercetin. To understand Sirt6 modulation by quercetin-based compounds, we analysed their binding and activity effects on Sirt6 and other Sirtuin isoforms and solved crystal structures of compound complexes with Sirt6 and Sirt2. We find that quercetin activates Sirt6 via the isoform-specific binding site for pyrrolo[1,2-a]quinoxalines. Its inhibitory effect on other isoforms is based on an alternative binding site at the active site entrance. Based on these insights, we identified isoquercetin as a ligand that can discriminate both sites and thus activates Sirt6 with increased specificity. Furthermore, we find that quercetin derivatives that inhibit rather than activate Sirt6 exploit the same general Sirt6 binding site as the activators, identifying it as a versatile allosteric site for Sirt6 modulation. Our results thus provide a structural basis for Sirtuin effects of quercetin-related compounds and helpful insights for Sirt6-targeted drug development. |
format | Online Article Text |
id | pubmed-6914789 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-69147892019-12-18 Structural basis for the activation and inhibition of Sirtuin 6 by quercetin and its derivatives You, Weijie Zheng, Wei Weiss, Sandra Chua, Katrin F. Steegborn, Clemens Sci Rep Article Mammalian Sirtuin 6 (Sirt6) is an NAD(+)-dependent protein deacylase regulating metabolism and chromatin homeostasis. Sirt6 activation protects against metabolic and aging-related diseases, and Sirt6 inhibition is considered a cancer therapy. Available Sirt6 modulators show insufficient potency and specificity, and even partially contradictory Sirt6 effects were reported for the plant flavone quercetin. To understand Sirt6 modulation by quercetin-based compounds, we analysed their binding and activity effects on Sirt6 and other Sirtuin isoforms and solved crystal structures of compound complexes with Sirt6 and Sirt2. We find that quercetin activates Sirt6 via the isoform-specific binding site for pyrrolo[1,2-a]quinoxalines. Its inhibitory effect on other isoforms is based on an alternative binding site at the active site entrance. Based on these insights, we identified isoquercetin as a ligand that can discriminate both sites and thus activates Sirt6 with increased specificity. Furthermore, we find that quercetin derivatives that inhibit rather than activate Sirt6 exploit the same general Sirt6 binding site as the activators, identifying it as a versatile allosteric site for Sirt6 modulation. Our results thus provide a structural basis for Sirtuin effects of quercetin-related compounds and helpful insights for Sirt6-targeted drug development. Nature Publishing Group UK 2019-12-16 /pmc/articles/PMC6914789/ /pubmed/31844103 http://dx.doi.org/10.1038/s41598-019-55654-1 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 You, Weijie Zheng, Wei Weiss, Sandra Chua, Katrin F. Steegborn, Clemens Structural basis for the activation and inhibition of Sirtuin 6 by quercetin and its derivatives |
title | Structural basis for the activation and inhibition of Sirtuin 6 by quercetin and its derivatives |
title_full | Structural basis for the activation and inhibition of Sirtuin 6 by quercetin and its derivatives |
title_fullStr | Structural basis for the activation and inhibition of Sirtuin 6 by quercetin and its derivatives |
title_full_unstemmed | Structural basis for the activation and inhibition of Sirtuin 6 by quercetin and its derivatives |
title_short | Structural basis for the activation and inhibition of Sirtuin 6 by quercetin and its derivatives |
title_sort | structural basis for the activation and inhibition of sirtuin 6 by quercetin and its derivatives |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914789/ https://www.ncbi.nlm.nih.gov/pubmed/31844103 http://dx.doi.org/10.1038/s41598-019-55654-1 |
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