| 题名 | Mechanism of action for small-molecule inhibitors of triacylglycerol synthesis |
| 作者 | |
| 通讯作者 | Liao，Maofu; Farese，Robert V.; Walther，Tobias C. |
| 发表日期 | 2023-05-29
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| DOI | |
| 发表期刊 | |
| EISSN | 2041-1723
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| 卷号 | 14期号:1 |
| 摘要 | Inhibitors of triacylglycerol (TG) synthesis have been developed to treat metabolism-related diseases, but we know little about their mechanisms of action. Here, we report cryo-EM structures of the TG-synthesis enzyme acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), a membrane bound O-acyltransferase (MBOAT), in complex with two different inhibitors, T863 and DGAT1IN1. Each inhibitor binds DGAT1's fatty acyl-CoA substrate binding tunnel that opens to the cytoplasmic side of the ER. T863 blocks access to the tunnel entrance, whereas DGAT1IN1 extends further into the enzyme, with an amide group interacting with more deeply buried catalytic residues. A survey of DGAT1 inhibitors revealed that this amide group may serve as a common pharmacophore for inhibition of MBOATs. The inhibitors were minimally active against the related MBOAT acyl-CoA:cholesterol acyltransferase 1 (ACAT1), yet a single-residue mutation sensitized ACAT1 for inhibition. Collectively, our studies provide a structural foundation for developing DGAT1 and other MBOAT inhibitors. |
| 相关链接 | [Scopus记录] |
| 收录类别 | |
| 语种 | 英语
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| 重要成果 | NI论文
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| 学校署名 | 通讯
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| 资助项目 | FP7 Health[GM124348]
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| WOS研究方向 | Science & Technology - Other Topics
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| WOS类目 | Multidisciplinary Sciences
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| WOS记录号 | WOS:001029731000029
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| 出版者 | |
| Scopus记录号 | 2-s2.0-85160489909
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| 来源库 | Scopus
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| 引用统计 |
被引频次[WOS]：3
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| 成果类型 | 期刊论文 |
| 条目标识符 | http://sustech.caswiz.com/handle/2SGJ60CL/536510 |
| 专题 | 生命科学学院 |
| 作者单位 | 1.Department of Molecular Metabolism,Harvard T.H. Chan School of Public Health,Boston,United States 2.Department of Cell Biology,Harvard Medical School,Boston,United States 3.Department of Biochemistry and Biophysics,College of Agriculture and Life Sciences,Texas A&M University,College Station,United States 4.Department of Biochemistry and Molecular Biotechnology,University of Massachusetts Chan Medical School,Worcester,United States 5.Cryo-EM Core Facility,University of Massachusetts Chan Medical School,Worcester,United States 6.School of Life Sciences,Southern University of Science and Technology,Shenzhen,China 7.Department of Molecular Metabolism,Harvard T.H. Chan School of Public Health,Boston,United States 8.Department of Cell Biology,Harvard Medical School,Boston,United States 9.Broad Institute of MIT and Harvard,Cambridge,United States 10.Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. robert@mskcc.org 11.Broad Institute of MIT and Harvard,Cambridge,United States 12.Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA 13.Howard Hughes Medical Institute,Boston,United States |
| 通讯作者单位 | 生命科学学院 |
| 推荐引用方式 GB/T 7714 |
Sui，Xuewu,Wang，Kun,Song，Kangkang,et al. Mechanism of action for small-molecule inhibitors of triacylglycerol synthesis[J]. Nature communications,2023,14(1).
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| APA |
Sui，Xuewu.,Wang，Kun.,Song，Kangkang.,Xu，Chen.,Song，Jiunn.,...&Walther，Tobias C..(2023).Mechanism of action for small-molecule inhibitors of triacylglycerol synthesis.Nature communications,14(1).
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| MLA |
Sui，Xuewu,et al."Mechanism of action for small-molecule inhibitors of triacylglycerol synthesis".Nature communications 14.1(2023).
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| 条目包含的文件 | ||||||
| 文件名称/大小 | 文献类型 | 版本类型 | 开放类型 | 使用许可 | 操作 | |
| s41467-023-38934-3(1（3580KB） | 期刊论文 | 作者接受稿 | 开放获取 | CC BY-NC-SA | 浏览 | |
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