Structural basis of inhibition of the human NAD+-dependent deacetylase SIRT5 by suramin
Structural basis of inhibition of the human NAD+-dependent deacetylase SIRT5 by suramin
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DOI：
10.1016/j.str.2007.02.002
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发表时间：
2007-03-01
期刊：
影响因子：
5.7
通讯作者：
Plotnikov, Alexander N.
中科院分区：
文献类型：
--
作者：
Schuetz, Anja;Min, Jinrong;Plotnikov, Alexander N.
Sirtuins是NAD（+）依赖的蛋白质脱乙酰酶，并且正在成为用于开发治疗人类代谢和神经系统疾病以及癌症的药物的分子靶标。迄今为止，已经鉴定了几种去乙酰化酶抑制剂和激活剂，但这些化合物如何调节去乙酰化酶活性的结构机制尚未确定。我们将苏拉明鉴定为与人SIRT 5结合的化合物，并显示其抑制SIRT 5 NAD（+）依赖性脱乙酰酶活性，IC 50值为22 μ M。为了深入了解抑制剂如何改变sirtuin功能，我们确定了SIRT 5的两种晶体结构，一种与ADP-核糖复合，另一种与苏拉明结合。我们的结构研究提供了一个合成的抑制性化合物在sirtuin活性位点揭示苏拉明结合到NAD（+），产品，和底物结合位点。最后，我们的结构可能使更有效的抑制剂的合理设计。
Sirtuins are NAD(+)-dependent protein deacetylases and are emerging as molecular targets for the development of pharmaceuticals to treat human metabolic and neurological diseases and cancer. To date, several sirtuin inhibitors and activators have been identified, but the structural mechanisms of how these compounds modulate sirtuin activity have not yet been determined. We identified suramin as a compound that binds to human SIRT5 and showed that it inhibits SIRT5 NAD(+)-dependent deacetylase activity with an IC50 value of 22 mu M. To provide insights into how sirtuin function is altered by inhibitors, we determined two crystal structures of SIRT5, one in complex with ADP-ribose, the other bound to suramin. Our structural studies provide a view of a synthetic inhibitory compound in a sirtuin active site revealing that suramin binds into the NAD(+), the product, and the substrate-binding site. Finally, our structures may enable the rational design of more potent inhibitors.