Tobias Rumpf 1 , Matthias Schiedel 1 , Berin Karaman 2 , Claudia Roessler 3 , Brian J. North 4 , Attila Lehotzky 5 , Judit Oláh 5 , Kathrin I. Ladwein 1 , Karin Schmidtkunz 1 , Markus Gajer 1 , Martin Pannek 6 , Clemens Steegborn 6 , David A. Sinclair 4 , Stefan Gerhardt 7 , Judit Ovádi 5 , Mike Schutkowski 3 , Wolfgang Sippl 2 , Oliver Einsle a , 7 , Manfred Jung b , 1
12 February 2015
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.
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.