Abstract
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. Nakasone et al. characterize a panel of ubistatin derivatives and show that ubistatins inhibit ubiquitination and shield ubiquitin conjugates from disassembly by a range of deubiquitinases and by the 26S proteasome. Ubistatin B penetrates cancer cells and alters the cellular ubiquitin landscape. The structures of ubiquitin complexes with ubistatin B and hemi-ubistatin revealed that hydrophobic and charge/polar interactions are critical for ubistatin:ubiquitin binding.
Original language | English (US) |
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Pages (from-to) | 1839-1855.e11 |
Journal | Structure |
Volume | 25 |
Issue number | 12 |
DOIs | |
State | Published - Dec 5 2017 |
Externally published | Yes |
Keywords
- NMR
- SANS
- deubiquitination
- polyubiquitin
- ubiquitin-proteasome system
- ubiquitination
- ubistatin
ASJC Scopus subject areas
- Structural Biology
- Molecular Biology