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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.
Bd. 6
(2015)
.
- S. 6263.
ISSN 2041-1723
DOI: https://doi.org/10.1038/ncomms7263
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.
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| Publikationsform: | Artikel in einer Zeitschrift |
|---|---|
| Begutachteter Beitrag: | Ja |
| Zusätzliche Informationen: | PubMed-ID: 20383002 |
| Institutionen der Universität: | Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Chemie > Lehrstuhl Biochemie > Lehrstuhl Biochemie I - Proteinbiochemie der Signaltransduktion - Univ.-Prof. Dr. Clemens Steegborn Fakultäten Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Chemie Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Chemie > Lehrstuhl Biochemie |
| Titel an der UBT entstanden: | Ja |
| Themengebiete aus DDC: | 500 Naturwissenschaften und Mathematik > 540 Chemie |
| Eingestellt am: | 20 Apr 2015 14:43 |
| Letzte Änderung: | 20 Apr 2015 14:43 |
| URI: | https://eref.uni-bayreuth.de/id/eprint/10436 |