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      Selective Sirt2 inhibition by ligand-induced rearrangement of the active site

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          Abstract

          Sirtuins are a highly conserved class of NAD +-dependent lysine deacylases. The human isotype Sirt2 has been implicated in the pathogenesis of cancer, inflammation and neurodegeneration, which makes the modulation of Sirt2 activity a promising strategy for pharmaceutical intervention. A rational basis for the development of optimized Sirt2 inhibitors is lacking so far. Here we present high-resolution structures of human Sirt2 in complex with highly selective drug-like inhibitors that show a unique inhibitory mechanism. Potency and the unprecedented Sirt2 selectivity are based on a ligand-induced structural rearrangement of the active site unveiling a yet-unexploited binding pocket. Application of the most potent Sirtuin-rearranging ligand, termed SirReal2, leads to tubulin hyperacetylation in HeLa cells and induces destabilization of the checkpoint protein BubR1, consistent with Sirt2 inhibition in vivo. Our structural insights into this unique mechanism of selective sirtuin inhibition provide the basis for further inhibitor development and selective tools for sirtuin biology.

          Abstract

          The involvement of the sirtuin family of lysine deacylases in disease, metabolism and ageing makes them promising pharmaceutical targets. Rumpf et al. present structures of human Sirt2 in complex with two highly selective drug-like inhibitors, and show that they act by rearranging the enzyme’s active site.

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          Most cited references 42

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          Linking crystallographic model and data quality.

          In macromolecular x-ray crystallography, refinement R values measure the agreement between observed and calculated data. Analogously, R(merge) values reporting on the agreement between multiple measurements of a given reflection are used to assess data quality. Here, we show that despite their widespread use, R(merge) values are poorly suited for determining the high-resolution limit and that current standard protocols discard much useful data. We introduce a statistic that estimates the correlation of an observed data set with the underlying (not measurable) true signal; this quantity, CC*, provides a single statistically valid guide for deciding which data are useful. CC* also can be used to assess model and data quality on the same scale, and this reveals when data quality is limiting model improvement.
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            Negative control of p53 by Sir2alpha promotes cell survival under stress.

            The NAD-dependent histone deacetylation of Sir2 connects cellular metabolism with gene silencing as well as aging in yeast. Here, we show that mammalian Sir2alpha physically interacts with p53 and attenuates p53-mediated functions. Nicotinamide (Vitamin B3) inhibits an NAD-dependent p53 deacetylation induced by Sir2alpha, and also enhances the p53 acetylation levels in vivo. Furthermore, Sir2alpha represses p53-dependent apoptosis in response to DNA damage and oxidative stress, whereas expression of a Sir2alpha point mutant increases the sensitivity of cells in the stress response. Thus, our findings implicate a p53 regulatory pathway mediated by mammalian Sir2alpha. These results have significant implications regarding an important role for Sir2alpha in modulating the sensitivity of cells in p53-dependent apoptotic response and the possible effect in cancer therapy.
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              T-Coffee: a web server for the multiple sequence alignment of protein and RNA sequences using structural information and homology extension

              This article introduces a new interface for T-Coffee, a consistency-based multiple sequence alignment program. This interface provides an easy and intuitive access to the most popular functionality of the package. These include the default T-Coffee mode for protein and nucleic acid sequences, the M-Coffee mode that allows combining the output of any other aligners, and template-based modes of T-Coffee that deliver high accuracy alignments while using structural or homology derived templates. These three available template modes are Expresso for the alignment of protein with a known 3D-Structure, R-Coffee to align RNA sequences with conserved secondary structures and PSI-Coffee to accurately align distantly related sequences using homology extension. The new server benefits from recent improvements of the T-Coffee algorithm and can align up to 150 sequences as long as 10 000 residues and is available from both http://www.tcoffee.org and its main mirror http://tcoffee.crg.cat.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Pub. Group
                2041-1723
                12 February 2015
                : 6
                Affiliations
                [1 ]Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg , Albertstraße 25, 79104 Freiburg im Breisgau, Germany
                [2 ]Institute for Pharmacy, Martin-Luther-University Halle-Wittenberg , Wolfgang-Langenbeck-Straße 4, 06120 Halle (Saale), Germany
                [3 ]Institute for Biochemistry and Biotechnology, Martin-Luther-University Halle-Wittenberg , Kurt-Mothes-Straße 3, 06120 Halle (Saale) Germany
                [4 ]Department of Genetics, Harvard Medical School , 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA
                [5 ]Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences , Magyar Tudósok körútja 2, H-1117 Budapest, Hungary
                [6 ]Department of Biochemistry, University of Bayreuth , Universitätsstraße 30, 95445 Bayreuth, Germany
                [7 ]Institute for Biochemistry and BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg im Breisgau , Albertstraße 21, 79104 Freiburg im Breisgau, Germany
                Author notes
                Article
                ncomms7263
                10.1038/ncomms7263
                4339887
                25672491
                Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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