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; Manfred Jung

doi:10.1038/ncomms7263

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, Manfred Jung

Research output: Contribution to journal › Article › peer-review

166 Scopus citations

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.

Original language	English (US)
Article number	6263
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7263
State	Published - Feb 2015
Externally published	Yes

All Science Journal Classification (ASJC) codes

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/ncomms7263

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Rumpf, T., Schiedel, M., Karaman, B., Roessler, C., North, B. J., Lehotzky, A., Oláh, J., Ladwein, K. I., Schmidtkunz, K., Gajer, M., Pannek, M., Steegborn, C., Sinclair, D. A., Gerhardt, S., Ovádi, J., Schutkowski, M., Sippl, W., Einsle, O., & Jung, M. (2015). Selective Sirt2 inhibition by ligand-induced rearrangement of the active site. Nature Communications, 6, [6263]. https://doi.org/10.1038/ncomms7263

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

In: Nature Communications, Vol. 6, 6263, 02.2015.

Research output: Contribution to journal › Article › peer-review

Rumpf, T, Schiedel, M, Karaman, B, Roessler, C, North, BJ, Lehotzky, A, Oláh, J, Ladwein, KI, Schmidtkunz, K, Gajer, M, Pannek, M, Steegborn, C, Sinclair, DA, Gerhardt, S, Ovádi, J, Schutkowski, M, Sippl, W, Einsle, O & Jung, M 2015, 'Selective Sirt2 inhibition by ligand-induced rearrangement of the active site', Nature Communications, vol. 6, 6263. https://doi.org/10.1038/ncomms7263

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. / Selective Sirt2 inhibition by ligand-induced rearrangement of the active site. In: Nature Communications. 2015 ; Vol. 6.

@article{ba9b1a55effe40adb956c95125ad3195,

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.",

author = "Tobias Rumpf and Matthias Schiedel and Berin Karaman and Claudia Roessler and North, {Brian J.} and Attila Lehotzky and Judit Ol{\'a}h and Ladwein, {Kathrin I.} and Karin Schmidtkunz and Markus Gajer and Martin Pannek and Clemens Steegborn and Sinclair, {David A.} and Stefan Gerhardt and Judit Ov{\'a}di and Mike Schutkowski and Wolfgang Sippl and Oliver Einsle and Manfred Jung",

note = "Funding Information: We thank C. Kambach (University of Bayreuth, Department of Biochemistry, Uni-versit{\"a}tsstra≈e 30, 95445 Bayreuth, Germany) for providing Sirt6. The studies have been supported by the Deutsche Forschungsgemeinschaft (Inhibitors: Ju295/8-1, Si868/6-1 structural work: SFB992 Medical Epigenetics, Project Z02) and the EU (cellular studies: SEtTReND, Nr. 241865, FP7 Health). M. Schutkowski was supported by grants from the BMBF (ProNet T3). D.A.S. was supported by grants from NIH/NIA (R01 AG028730 and R01 AG019719), the Glenn Foundation for Medical Research, the United Mitochondrial Disease Foundation, The Juvenile Diabetes foundation and a gift from the Schulak family. B.J.N. was supported by BIDMC/Harvard Translational Research in Aging Training Program (T32 AG023480). C.S. and M.P. thank Oberfrankenstiftung for support. J. Ov{\'a}di was supported by the Hungarian National Scientific Research Fund Grants OTKA T-101039 and Richter Gedeon Nyrt (4700147899). J. Ov{\'a}di, W.S. and M.J. thank the COST Action TD0905 {\textquoteleft}Epigenetics—from bench to bedside{\textquoteright} for support. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved.",

year = "2015",

month = feb,

doi = "10.1038/ncomms7263",

language = "English (US)",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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TY - JOUR

T1 - Selective Sirt2 inhibition by ligand-induced rearrangement of the active site

AU - Rumpf, Tobias

AU - Schiedel, Matthias

AU - Karaman, Berin

AU - Roessler, Claudia

AU - North, Brian J.

AU - Lehotzky, Attila

AU - Oláh, Judit

AU - Ladwein, Kathrin I.

AU - Schmidtkunz, Karin

AU - Gajer, Markus

AU - Pannek, Martin

AU - Steegborn, Clemens

AU - Sinclair, David A.

AU - Gerhardt, Stefan

AU - Ovádi, Judit

AU - Schutkowski, Mike

AU - Sippl, Wolfgang

AU - Einsle, Oliver

AU - Jung, Manfred

N1 - Funding Information: We thank C. Kambach (University of Bayreuth, Department of Biochemistry, Uni-versitätsstra≈e 30, 95445 Bayreuth, Germany) for providing Sirt6. The studies have been supported by the Deutsche Forschungsgemeinschaft (Inhibitors: Ju295/8-1, Si868/6-1 structural work: SFB992 Medical Epigenetics, Project Z02) and the EU (cellular studies: SEtTReND, Nr. 241865, FP7 Health). M. Schutkowski was supported by grants from the BMBF (ProNet T3). D.A.S. was supported by grants from NIH/NIA (R01 AG028730 and R01 AG019719), the Glenn Foundation for Medical Research, the United Mitochondrial Disease Foundation, The Juvenile Diabetes foundation and a gift from the Schulak family. B.J.N. was supported by BIDMC/Harvard Translational Research in Aging Training Program (T32 AG023480). C.S. and M.P. thank Oberfrankenstiftung for support. J. Ovádi was supported by the Hungarian National Scientific Research Fund Grants OTKA T-101039 and Richter Gedeon Nyrt (4700147899). J. Ovádi, W.S. and M.J. thank the COST Action TD0905 ‘Epigenetics—from bench to bedside’ for support. Publisher Copyright: © 2015 Macmillan Publishers Limited. All rights reserved.

PY - 2015/2

Y1 - 2015/2

N2 - 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.

AB - 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.

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

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