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Structural Basis for Activation of Human Sirtuin 6 by Fluvastatin

Title data

You, Weijie ; Steegborn, Clemens:
Structural Basis for Activation of Human Sirtuin 6 by Fluvastatin.
In: ACS Medicinal Chemistry Letters. Vol. 11 (12 November 2020) Issue 11 . - pp. 2285-2289.
ISSN 1948-5875
DOI: https://doi.org/10.1021/acsmedchemlett.0c00407

Abstract in another language

Sirtuins are NAD-dependent protein lysine deacylases that are considered attractive drug targets for aging-related diseases. Sirt6 deacetylates, e.g., transcription factors and histone H3, and regulates metabolic processes and stress responses. It has been implicated in lifespan extension and tumor suppression. Sirt6 deacetylase activity can be stimulated with small molecules, and fluvastatin, an FDA-approved synthetic statin, was recently described as a novel Sirt6 activator. We studied the molecular details of this effect on Sirt6 in deacylation assays and by solving a crystal structure of a Sirt6/fluvastatin complex. We find that fluvastatin inhibits Sirt1-3 at higher concentrations but has a unique, activating effect on Sirt6. The complex structure reveals that fluvastatin occupies the Sirt6 substrate acyl channel exit, similar to other, unrelated activator families, providing interaction details that will support the development of potent, druglike Sirt6 activators.

Further data

Item Type: Article in a journal
Refereed: Yes
Institutions of the University: Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry > Chair Biochemistry - Univ.-Prof. Dr. Clemens Steegborn
Result of work at the UBT: Yes
DDC Subjects: 500 Science > 540 Chemistry
500 Science > 570 Life sciences, biology
Date Deposited: 26 Mar 2021 08:59
Last Modified: 26 Mar 2021 08:59
URI: https://eref.uni-bayreuth.de/id/eprint/64330