6ZU4

Human Sirt6 13-308 in complex with ADP-ribose and the activator fluvastatin

Summary for 6ZU4

• Entry DOI: 10.2210/pdb6zu4/pdb
• Descriptor: NAD-dependent protein deacetylase sirtuin-6, [(2R,3S,4R,5R)-5-(6-AMINOPURIN-9-YL)-3,4-DIHYDROXY-OXOLAN-2-YL]METHYL [HYDROXY-[[(2R,3S,4R,5S)-3,4,5-TRIHYDROXYOXOLAN-2-YL]METHOXY]PHOSPHORYL] HYDROGEN PHOSPHATE, ZINC ION, ... (7 entities in total)
• Functional Keywords: deacylase, activator, allosteric, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 69972.86

Authors

You, W.,Steegborn, C. (deposition date: 2020-07-21, release date: 2020-11-18, Last modification date: 2024-01-31)

Primary citation

You, W.,Steegborn, C.
Structural Basis for Activation of Human Sirtuin 6 by Fluvastatin.
Acs Med.Chem.Lett., 11:2285-2289, 2020

PubMed Abstract: 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.

PubMed: 33214841
DOI: 10.1021/acsmedchemlett.0c00407

Experimental method

X-RAY DIFFRACTION (2.46 Å)