Structural basis of inhibition of the human NAD+-dependent deacetylase SIRT5 by suramin

被引:209
作者
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. [1 ]
机构
[1] Univ Toronto, Struct Genom Consortium, 100 Coll St, Toronto, ON M5G 1L5, Canada
[2] SUNY Stony Brook, Dept Biochem & Cell Biol, Stony Brook, NY 11794 USA
[3] Univ Toronto, Banting & Best Dept Med Res, Toronto, ON M5G 1L6, Canada
[4] Univ Toronto, Dept Med Genet & Microbiol, Toronto, ON M5G 1L6, Canada
[5] Univ Toronto, Dept Physiol, Toronto, ON M5G 1L6, Canada
基金
英国惠康基金;
关键词
D O I
10.1016/j.str.2007.02.002
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:377 / 389
页数:13
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