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DOI | 10.1038/nature23645 |
An allosteric mechanism for potent inhibition of human ATP-citrate lyase | |
Wei, Jia1; Leit, Silvana2; Kuai, Jun2; Therrien, Eric3; Rafi, Salma3; Harwood, H. James, Jr.2; DeLaBarre, Byron2; Tong, Liang1 | |
2019-04-25 | |
发表期刊 | NATURE |
ISSN | 0028-0836 |
EISSN | 1476-4687 |
出版年 | 2019 |
卷号 | 568期号:7753页码:566-+ |
文章类型 | Article |
语种 | 英语 |
国家 | USA |
英文摘要 | ATP-citrate lyase (ACLY) is a central metabolic enzyme and catalyses the ATP-dependent conversion of citrate and coenzyme A (CoA) to oxaloacetate and acetyl-CoA(1-5). The acetyl-CoA product is crucial for the metabolism of fatty acids(6,7), the biosynthesis of cholesterol(8), and the acetylation and prenylation of proteins(9,10). There has been considerable interest in ACLY as a target for anticancer drugs, because many cancer cells depend on its activity for proliferation(2,5,11). ACLY is also a target against dyslipidaemia and hepatic steatosis, with a compound currently in phase 3 clinical trials(4,5). Many inhibitors of ACLY have been reported, but most of them have weak activity(5). Here we report the development of a series of low nanomolar, small-molecule inhibitors of human ACLY. We have also determined the structure of the full-length human ACLY homo-tetramer in complex with one of these inhibitors (NDI-091143) by cryo-electron microscopy, which reveals an unexpected mechanism of inhibition. The compound is located in an allosteric, mostly hydrophobic cavity next to the citrate-binding site, and requires extensive conformational changes in the enzyme that indirectly disrupt citrate binding. The observed binding mode is supported by and explains the structure-activity relationships of these compounds. This allosteric site greatly enhances the 'druggability' of ACLY and represents an attractive target for the development of new ACLY inhibitors. |
领域 | 地球科学 ; 气候变化 ; 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000465594200054 |
WOS关键词 | CATALYTIC RESIDUES ; SYNTHASE ; BINDING ; VISUALIZATION ; ACCURATE ; COMPLEX ; GLUCOSE ; SITE |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/202789 |
专题 | 地球科学 资源环境科学 气候变化 |
作者单位 | 1.Columbia Univ, Dept Biol Sci, New York, NY 10027 USA; 2.Nimbus Therapeut, Cambridge, MA USA; 3.Schrodinger LLC, New York, NY USA |
推荐引用方式 GB/T 7714 | Wei, Jia,Leit, Silvana,Kuai, Jun,et al. An allosteric mechanism for potent inhibition of human ATP-citrate lyase[J]. NATURE,2019,568(7753):566-+. |
APA | Wei, Jia.,Leit, Silvana.,Kuai, Jun.,Therrien, Eric.,Rafi, Salma.,...&Tong, Liang.(2019).An allosteric mechanism for potent inhibition of human ATP-citrate lyase.NATURE,568(7753),566-+. |
MLA | Wei, Jia,et al."An allosteric mechanism for potent inhibition of human ATP-citrate lyase".NATURE 568.7753(2019):566-+. |
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