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

Tobias Rumpf, Matthias Schiedel, Berin Karaman, Claudia Roessler, Brian J. North, Attila Lehotzky, Judit Oláh, Kathrin I. Ladwein, Karin Schmidtkunz, Markus Gajer, Martin Pannek, Clemens Steegborn, David A. Sinclair, Stefan Gerhardt, Judit Ovádi, Mike Schutkowski, Wolfgang Sippl, Oliver Einsle () and Manfred Jung ()
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Tobias Rumpf: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg
Matthias Schiedel: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg
Berin Karaman: Institute for Pharmacy, Martin-Luther-University Halle-Wittenberg
Claudia Roessler: Institute for Biochemistry and Biotechnology, Martin-Luther-University Halle-Wittenberg
Brian J. North: Harvard Medical School
Attila Lehotzky: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences
Judit Oláh: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences
Kathrin I. Ladwein: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg
Karin Schmidtkunz: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg
Markus Gajer: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg
Martin Pannek: University of Bayreuth
Clemens Steegborn: University of Bayreuth
David A. Sinclair: Harvard Medical School
Stefan Gerhardt: Institute for Biochemistry and BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg im Breisgau
Judit Ovádi: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences
Mike Schutkowski: Institute for Biochemistry and Biotechnology, Martin-Luther-University Halle-Wittenberg
Wolfgang Sippl: Institute for Pharmacy, Martin-Luther-University Halle-Wittenberg
Oliver Einsle: Institute for Biochemistry and BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg im Breisgau
Manfred Jung: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7263

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