Structural Basis for Activation of Human Sirtuin 6 by Fluvastatin

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Sirtuins are NAD+-dependent protein deacetylases and targets for aging-related diseases.
• Sirt6 plays roles in metabolism, stress response, lifespan extension, and tumor suppression.
• Small molecules can stimulate Sirt6 deacetylase activity, with fluvastatin identified as a novel activator.

Purpose of the Study:

• To investigate the molecular mechanisms by which fluvastatin activates Sirt6.
• To elucidate the structural basis of the Sirt6-fluvastatin interaction.
• To guide the development of potent and druglike Sirt6 activators.

Main Methods:

• Deacylation assays were performed to study Sirt6 activity.
• Crystal structure of a Sirt6/fluvastatin complex was determined.
• Biochemical and structural analyses were conducted.

Main Results:

• Fluvastatin uniquely activates Sirt6, while inhibiting Sirt1-3 at higher concentrations.
• The crystal structure revealed fluvastatin binding at the Sirt6 substrate acyl channel exit.
• This binding mode is similar to other unrelated Sirt6 activator families.

Conclusions:

• Fluvastatin's interaction with Sirt6 provides a structural basis for its activation.
• The findings support the development of novel, potent, and druglike Sirt6 activators.
• Targeting Sirt6 with activators holds promise for treating age-related diseases.