Schuetz Anja, Min Jinrong, Antoshenko Tatiana, Wang Chia-Lin, Allali-Hassani Abdellah, Dong Aiping, Loppnau Peter, Vedadi Masoud, Bochkarev Alexey, Sternglanz Rolf, Plotnikov Alexander N
Structural Genomics Consortium, University of Toronto, 100 College Street, Toronto, Ontario M5G 1L5, Canada.
Structure. 2007 Mar;15(3):377-89. doi: 10.1016/j.str.2007.02.002.
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 IC(50) value of 22 microM. 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.
沉默调节蛋白是依赖烟酰胺腺嘌呤二核苷酸（NAD(+)）的蛋白质脱乙酰酶，正逐渐成为开发治疗人类代谢、神经疾病及癌症药物的分子靶点。迄今为止，已鉴定出多种沉默调节蛋白抑制剂和激活剂，但这些化合物调节沉默调节蛋白活性的结构机制尚未明确。我们鉴定出苏拉明是一种能与人SIRT5结合的化合物，并表明它能抑制SIRT5依赖NAD(+)的脱乙酰酶活性，半数抑制浓度（IC(50)）值为22微摩尔。为深入了解抑制剂如何改变沉默调节蛋白的功能，我们测定了SIRT5的两个晶体结构，一个与ADP-核糖形成复合物，另一个与苏拉明结合。我们的结构研究展示了沉默调节蛋白活性位点中的一种合成抑制性化合物，表明苏拉明结合到NAD(+)、产物及底物结合位点。最后，我们的结构可能有助于更合理地设计更有效的抑制剂。
