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.

中文翻译：

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氟伐他汀激活人 Sirtuin 6 的结构基础

Sirtuins 是 NAD ⁺依赖的蛋白质赖氨酸脱酰酶，被认为是治疗衰老相关疾病的有吸引力的药物靶点。Sirt6 去乙酰化，例如转录因子和组蛋白 H3，并调节代谢过程和应激反应。它与寿命延长和肿瘤抑制有关。Sirt6 脱乙酰酶活性可以用小分子刺激，而氟伐他汀是一种 FDA 批准的合成他汀类药物，最近被描述为一种新型的 Sirt6 激活剂。我们在脱酰化试验中并通过解析 Sirt6/氟伐他汀复合物的晶体结构研究了这种对 Sirt6 影响的分子细节。我们发现氟伐他汀在较高浓度下抑制 Sirt1-3，但对 Sirt6 具有独特的激活作用。复杂的结构表明氟伐他汀占据了Sirt6底物酰基通道出口，与其他类似，