Evidence for a common mechanism of SIRT1 regulation by allosteric activators.
Evidence for a common mechanism of SIRT1 regulation by allosteric activators.
复制标题
DOI：
10.1126/science.1231097
复制
发表时间：
2013-03-08
期刊：
影响因子：
--
通讯作者：
Sinclair DA
中科院分区：
文献类型：
--
作者：
Hubbard BP;Gomes AP;Dai H;Li J;Case AW;Considine T;Riera TV;Lee JE;E SY;Lamming DW;Pentelute BL;Schuman ER;Stevens LA;Ling AJ;Armour SM;Michan S;Zhao H;Jiang Y;Sweitzer SM;Blum CA;Disch JS;Ng PY;Howitz KT;Rolo AP;Hamuro Y;Moss J;Perni RB;Ellis JL;Vlasuk GP;Sinclair DA
治疗多种年龄相关疾病的分子将对全球健康和经济产生重大影响。SIRT 1脱乙酰酶在这方面作为药物设计的靶点引起了人们的注意。然而，围绕sirtuin激活化合物（STAC）的机制存在争议。我们发现，在SIRT 1底物如PGC-1α和FOXO 3a中发现的特异性疏水基序有助于STAC激活SIRT 1。SIRT 1中的单个氨基酸Glu 230位于结构化的N-末端结构域中，对于所有先前报道的STAC支架和一类新的化学上不同的激活剂的激活至关重要。在用活化缺陷型SIRT 1重建的原代细胞中，STAC的代谢作用被阻断。因此，SIRT 1可以通过化学上不同的STAC所共有的变构机制直接活化。
A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs). We found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1α and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu230, located in a structured N-terminal domain, was critical for activation by all previously reported STAC scaffolds and a new class of chemically distinct activators. In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs.
登录
查看更多内容
影响因子：
4.8
作者：
Pacholec, Michelle;Bleasdale, John E.;Ahn, Kay
通讯作者：
Ahn, Kay
影响因子：
2.7
作者：
SUGAWARA, K;OYAMA, F
通讯作者：
OYAMA, F
影响因子：
4.8
作者：
Lan, Fan;Cacicedo, Jose M.;Ido, Yasuo
通讯作者：
Ido, Yasuo
影响因子：
3
作者：
Beher, Dirk;Wu, John;Wang, Minghan
通讯作者：
Wang, Minghan
影响因子：
64.8
作者：
Rodgers, JT;Lerin, C;Puigserver, P
通讯作者：
Puigserver, P