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DOI | 10.1038/s41467-018-05737-w |
Long-range allosteric regulation of the human 26S proteasome by 20S proteasome-targeting cancer drugs | |
Haselbach, David; Schrader, Jil; Lambrecht, Felix; Henneberg, Fabian; Chari, Ashwin; Stark, Holger | |
2017-05-25 | |
发表期刊 | NATURE COMMUNICATIONS
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ISSN | 2041-1723 |
出版年 | 2017 |
卷号 | 8 |
文章类型 | Article |
语种 | 英语 |
国家 | Germany |
英文摘要 | The proteasome holoenzyme is the major non-lysosomal protease; its proteolytic activity is essential for cellular homeostasis. Thus, it is an attractive target for the development of chemotherapeutics. While the structural basis of core particle (CP) inhibitors is largely understood, their structural impact on the proteasome holoenzyme remains entirely elusive. Here, we determined the structure of the 26S proteasome with and without the inhibitor Oprozomib. Drug binding modifies the energy landscape of conformational motion in the proteasome regulatory particle (RP). Structurally, the energy barrier created by Oprozomib triggers a long-range allosteric regulation, resulting in the stabilization of a non-productive state. Thereby, the chemical drug-binding signal is converted, propagated and amplified into structural changes over a distance of more than 150 angstrom from the proteolytic site to the ubiquitin receptor Rpn10. The direct visualization of changes in conformational dynamics upon drug binding allows new ways to screen and develop future allosteric proteasome inhibitors. |
领域 | 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000401965600001 |
WOS关键词 | GENERATION ; RESOLUTION ; PARTICLE |
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/203976 |
专题 | 资源环境科学 |
作者单位 | Max Planck Inst Biophys Chem, Dept Struct Dynam, Fassberg 11, D-37077 Gottingen, Germany |
推荐引用方式 GB/T 7714 | Haselbach, David,Schrader, Jil,Lambrecht, Felix,et al. Long-range allosteric regulation of the human 26S proteasome by 20S proteasome-targeting cancer drugs[J]. NATURE COMMUNICATIONS,2017,8. |
APA | Haselbach, David,Schrader, Jil,Lambrecht, Felix,Henneberg, Fabian,Chari, Ashwin,&Stark, Holger.(2017).Long-range allosteric regulation of the human 26S proteasome by 20S proteasome-targeting cancer drugs.NATURE COMMUNICATIONS,8. |
MLA | Haselbach, David,et al."Long-range allosteric regulation of the human 26S proteasome by 20S proteasome-targeting cancer drugs".NATURE COMMUNICATIONS 8(2017). |
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