title: 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.
authors: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg, Albertstraße 25, 79104 Freiburg im Breisgau, Germany.
authors: Tobias
authors: T
authors: Rumpf
authors: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg, Albertstraße 25, 79104 Freiburg im Breisgau, Germany.
authors: Matthias
authors: M
authors: Schiedel
authors: Institute for Pharmacy, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Straße 4, 06120 Halle (Saale), Germany.
authors: Berin
authors: B
authors: Karaman
authors: Institute for Biochemistry and Biotechnology, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Straße 3, 06120 Halle (Saale) Germany.
authors: Claudia
authors: C
authors: Roessler
authors: Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
authors: Brian J
authors: BJ
authors: North
authors: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok körútja 2, H-1117 Budapest, Hungary.
authors: Attila
authors: A
authors: Lehotzky
authors: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok körútja 2, H-1117 Budapest, Hungary.
authors: Judit
authors: J
authors: Oláh
authors: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg, Albertstraße 25, 79104 Freiburg im Breisgau, Germany.
authors: Kathrin I
authors: KI
authors: Ladwein
authors: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg, Albertstraße 25, 79104 Freiburg im Breisgau, Germany.
authors: Karin
authors: K
authors: Schmidtkunz
authors: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg, Albertstraße 25, 79104 Freiburg im Breisgau, Germany.
authors: Markus
authors: M
authors: Gajer
authors: Department of Biochemistry, University of Bayreuth, Universitätsstraße 30, 95445 Bayreuth, Germany.
authors: Martin
authors: M
authors: Pannek
authors: Department of Biochemistry, University of Bayreuth, Universitätsstraße 30, 95445 Bayreuth, Germany.
authors: Clemens
authors: C
authors: Steegborn
authors: Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
authors: David A
authors: DA
authors: Sinclair
authors: Institute for Biochemistry and BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg im Breisgau, Albertstraße 21, 79104 Freiburg im Breisgau, Germany.
authors: Stefan
authors: S
authors: Gerhardt
authors: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok körútja 2, H-1117 Budapest, Hungary.
authors: Judit
authors: J
authors: Ovádi
authors: Institute for Biochemistry and Biotechnology, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Straße 3, 06120 Halle (Saale) Germany.
authors: Mike
authors: M
authors: Schutkowski
authors: Institute for Pharmacy, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Straße 4, 06120 Halle (Saale), Germany.
authors: Wolfgang
authors: W
authors: Sippl
authors: Institute for Biochemistry and BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg im Breisgau, Albertstraße 21, 79104 Freiburg im Breisgau, Germany.
authors: Oliver
authors: O
authors: Einsle
authors: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg, Albertstraße 25, 79104 Freiburg im Breisgau, Germany.
authors: Manfred
authors: M
authors: Jung
mesh_terms: D000081:Acetamides / Q000737:chemistry / Q000494:pharmacology; D000595:Amino Acid Sequence; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000081:Acetamides; D004791:Enzyme Inhibitors; D008024:Ligands; C000609012:SirReal2; D013844:Thiazoles; C474199:SIRT2 protein, human; D056565:Sirtuin 2