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

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

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Title: Selective Sirt2 inhibition by ligand-induced rearrangement of the active site
Author: Rumpf, Tobias; Schiedel, Matthias; Karaman, Berin; Roessler, Claudia; North, Brian J.; Lehotzky, Attila; Oláh, Judit; Ladwein, Kathrin I.; Schmidtkunz, Karin; Gajer, Markus; Pannek, Martin; Steegborn, Clemens; Sinclair, David A.; Gerhardt, Stefan; Ovádi, Judit; Schutkowski, Mike; Sippl, Wolfgang; Einsle, Oliver; Jung, Manfred

Note: Order does not necessarily reflect citation order of authors.

Citation: Rumpf, T., M. Schiedel, B. Karaman, C. Roessler, B. J. North, A. Lehotzky, J. Oláh, et al. 2015. “Selective Sirt2 inhibition by ligand-induced rearrangement of the active site.” Nature Communications 6 (1): 6263. doi:10.1038/ncomms7263. http://dx.doi.org/10.1038/ncomms7263.
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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.
Published Version: doi:10.1038/ncomms7263
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4339887/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:14351353
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