Literatur vom gleichen Autor/der gleichen Autor*in
plus bei Google Scholar

Bibliografische Daten exportieren
 

Structural basis for the activation and inhibition of Sirtuin 6 by quercetin and its derivatives

Titelangaben

You, Weijie ; Zheng, Wei ; Weiß, Sandra ; Chua, Katrin F. ; Steegborn, Clemens:
Structural basis for the activation and inhibition of Sirtuin 6 by quercetin and its derivatives.
In: Scientific Reports. Bd. 9 (2019) . - 19176.
ISSN 2045-2322
DOI: https://doi.org/10.1038/s41598-019-55654-1

Volltext

Link zum Volltext (externe URL): Volltext

Angaben zu Projekten

Projekttitel:
Offizieller Projekttitel
Projekt-ID
Open Access Publizieren
Ohne Angabe

Abstract

Mammalian Sirtuin 6 (Sirt6) is an NAD+-dependent protein deacylase regulating metabolism and chromatin homeostasis. Sirt6 activation protects against metabolic and aging-related diseases, and Sirt6 inhibition is considered a cancer therapy. Available Sirt6 modulators show insufficient potency and specificity, and even partially contradictory Sirt6 effects were reported for the plant flavone quercetin. To understand Sirt6 modulation by quercetin-based compounds, we analysed their binding and activity effects on Sirt6 and other Sirtuin isoforms and solved crystal structures of compound complexes with Sirt6 and Sirt2. We find that quercetin activates Sirt6 via the isoform-specific binding site for pyrrolo[1,2-a]quinoxalines. Its inhibitory effect on other isoforms is based on an alternative binding site at the active site entrance. Based on these insights, we identified isoquercetin as a ligand that can discriminate both sites and thus activates Sirt6 with increased specificity. Furthermore, we find that quercetin derivatives that inhibit rather than activate Sirt6 exploit the same general Sirt6 binding site as the activators, identifying it as a versatile allosteric site for Sirt6 modulation. Our results thus provide a structural basis for Sirtuin effects of quercetin-related compounds and helpful insights for Sirt6-targeted drug development.

Weitere Angaben

Publikationsform: Artikel in einer Zeitschrift
Begutachteter Beitrag: Ja
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
Eingestellt am: 28 Mär 2020 22:00
Letzte Änderung: 25 Aug 2023 06:30
URI: https://eref.uni-bayreuth.de/id/eprint/54741