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

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.

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Pub. Group

ISSN (Electronic): 2041-1723

Publication date (Electronic): 12 February 2015

Volume: 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

[a ] einsle@ 123456biochemie.uni-freiburg.de

[b ] manfred.jung@ 123456pharmazie.uni-freiburg.de

Article

Publisher Item ID: ncomms7263

DOI: 10.1038/ncomms7263

PMC ID: 4339887

PubMed ID: 25672491

Copyright statement: Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

License:

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/

Categories

Subject: Article