期刊
STRUCTURE
卷 25, 期 12, 页码 1839-+出版社
CELL PRESS
DOI: 10.1016/j.str.2017.10.007
关键词
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资金
- NCI Initiative for Chemical Genetics, NIH [N01-CO-12400]
- NIH [GM065334, GM095755, GM075061, DK079307]
- ISF [909-14]
- Cystic Fibrosis Foundation Therapeutics grant BRODSK13XXO
- Fulbright postdoctoral fellowship
- NSF [DBI1040158, DMR-0944772]
The discovery of ubistatins, small molecules that impair proteasomal degradation of proteins by directly binding to polyubiquitin, makes ubiquitin itself a potential therapeutic target. Although ubistatins have the potential for drug development and clinical applications, the lack of structural details of ubiquitin-ubistatin interactions has impeded their development. Here, we characterized a panel of new ubistatin derivatives using functional and binding assays. The structures of ubiquitin complexes with ubistatin B and hemi-ubistatin revealed direct interactions with ubiquitin's hydrophobic surface patch and the basic/polar residues surrounding it. Ubistatin B binds ubiquitin and diubiquitin tighter than a high-affinity ubiquitin receptor and shows strong preference for K48 linkages over K11 and K63. Furthermore, ubistatin B shields ubiquitin conjugates from disassembly by a range of deubiquitinases and by the 26S proteasome. Finally, ubistatin B penetrates cancer cells and alters the cellular ubiquitin landscape. These findings highlight versatile properties of ubistatins and have implications for their future development and use in targeting ubiquitin-signaling pathways.
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