Discovery and Mechanism Study of SIRT1 Activators that Promote the Deacetylation of Fluorophore-Labeled Substrate
文献类型：期刊论文
| 作者 | Wu, Jiahui6; Zhang, Dengyou5; Chen, Lei6; Li, Jianneng2; Wang, Jianling4; Ning, Chengqing3; Yu, Niefang3; Zhao, Fei5; Chen, Dongying4 ; Chen, Xiaoyan1
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2013-02-14 |
| 卷号 | 56期号:3页码:761-780 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/jm301032j |
| 文献子类 | Article |
| 英文摘要 | SIRT1 is an NAD(+)-dependent deacetylase, whose activators have potential therapeutic applications in age-related diseases. Here we report a new class of SIRT1 activators. The activation is dependent on the fluorophore labeled to the substrate. To elucidate the activation mechanism, we solved the crystal structure of SIRT3/ac-RHKKac-AMC complex. The structure revealed that the fluorophore blocked the H-bond formation and created a cavity between the substrate and the Rossmann fold. We built the SIRT1/ac-RHKKac-AMC complex model based on the crystal structure. K-m and K-d determinations demonstrated that the fluorophore decreased the peptide binding affinity. The binding modes of SIRT1 activators indicated that a portion of the activators interacts with the fluorophore through pi-stacking, while the portion inserts into the cavity or interacts with the Rossmann fold, thus increasing the substrate affinity. Our study provides new insights into the mechanism of SIRT1 activation and may aid the design of novel SIRT1 activators. |
| WOS关键词 | SMALL-MOLECULE ACTIVATORS ; DEPENDENT PROTEIN DEACETYLASES ; LIFE-SPAN ; DROSOPHILA-MELANOGASTER ; CRYSTAL-STRUCTURE ; STRUCTURAL BASIS ; RESVERATROL ; SIRTUINS ; INHIBITORS ; COMPLEX |
| 资助项目 | National Science Fund[21021063] ; National Science Fund[91229204] ; Science and Technology Commission of Shanghai Municipality[08JC1422100] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000315182100013 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277732]  |
| 专题 | 药物化学研究室 药理学第三研究室 |
| 通讯作者 | Liu, Dongxiang |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Metab & Pharmacokinet, Shanghai 201203, Peoples R China; 2.Fudan Univ, Sch Life Sci, Shanghai 200433, Peoples R China; 3.Cent S Univ, Sch Pharmaceut Sci, Inst Mol Design & Drug Discovery, Changsha 410078, Hunan, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Analyt Chem, Shanghai 201203, Peoples R China; 5.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China; 6.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Pharmacol 3, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Wu, Jiahui,Zhang, Dengyou,Chen, Lei,et al. Discovery and Mechanism Study of SIRT1 Activators that Promote the Deacetylation of Fluorophore-Labeled Substrate[J]. JOURNAL OF MEDICINAL CHEMISTRY,2013,56(3):761-780. |
| APA | Wu, Jiahui.,Zhang, Dengyou.,Chen, Lei.,Li, Jianneng.,Wang, Jianling.,...&Liu, Dongxiang.(2013).Discovery and Mechanism Study of SIRT1 Activators that Promote the Deacetylation of Fluorophore-Labeled Substrate.JOURNAL OF MEDICINAL CHEMISTRY,56(3),761-780. |
| MLA | Wu, Jiahui,et al."Discovery and Mechanism Study of SIRT1 Activators that Promote the Deacetylation of Fluorophore-Labeled Substrate".JOURNAL OF MEDICINAL CHEMISTRY 56.3(2013):761-780. |
入库方式： OAI收割
来源：上海药物研究所
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