期刊
SCIENCE
卷 339, 期 6119, 页码 590-595出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1230161
关键词
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资金
- Canadian Institutes for Health Research [MOP-111149, MOP-13494, MOP-57795, MOP-102536, 1097737]
- NIH-National Institute of Neurological Disorders and Stroke [1R01NS072420-01]
- Canada Research Chairs in Structural Principles of Signal Transduction
- Canadian Foundation for Innovation, Systems and Synthetic Biology
- Molecular Signatures
- Canada Foundation for Innovation
- Genome Canada through the Ontario Genomics Institute
- GlaxoSmithKline
- Karolinska Institutet
- Knut and Alice Wallenberg Foundation
- Ontario Innovation Trust
- Ontario Ministry for Research and Innovation
- Merck Co.
- Novartis Research Foundation
- Swedish Agency for Innovation Systems
- Swedish Foundation for Strategic Research
- Wellcome Trust
The ubiquitin system regulates virtually all aspects of cellular function. We report a method to target the myriad enzymes that govern ubiquitination of protein substrates. We used massively diverse combinatorial libraries of ubiquitin variants to develop inhibitors of four deubiquitinases (DUBs) and analyzed the DUB-inhibitor complexes with crystallography. We extended the selection strategy to the ubiquitin conjugating (E2) and ubiquitin ligase (E3) enzymes and found that ubiquitin variants can also enhance enzyme activity. Last, we showed that ubiquitin variants can bind selectively to ubiquitin-binding domains. Ubiquitin variants exhibit selective function in cells and thus enable orthogonal modulation of specific enzymatic steps in the ubiquitin system.
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