TY - JOUR
T1 - Structural Basis for the Inhibitory Effects of Ubistatins in the Ubiquitin-Proteasome Pathway
AU - Nakasone, Mark A.
AU - Lewis, Timothy A.
AU - Walker, Olivier
AU - Thakur, Anita
AU - Mansour, Wissam
AU - Castañeda, Carlos A.
AU - Goeckeler-Fried, Jennifer L.
AU - Parlati, Frank
AU - Chou, Tsui-Fen
AU - Hayat, Ortal
AU - Zhang, Daoning
AU - Camara, Christina M.
AU - Bonn, Steven M.
AU - Nowicka, Urszula K.
AU - Krueger, Susan
AU - Glickman, Michael H.
AU - Brodsky, Jeffrey L.
AU - Deshaies, Raymond J.
AU - Fushman, David
N1 - Funding for this research was provided by:
NCI
NIH (GM065334, GM095755, GM075061, DK079307)
ISF (909-14)
Cystic Fibrosis Foundation Therapeutics (BRODSK13XXO)
NSF (DBI1040158)
Copyright © 2017 Elsevier Ltd. All rights reserved.
PY - 2017/12/5
Y1 - 2017/12/5
N2 - 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.
AB - 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.
KW - Binding Sites
KW - Cell Line
KW - HeLa Cells
KW - Humans
KW - Molecular Docking Simulation
KW - Proteasome Endopeptidase Complex/chemistry
KW - Protein Binding
KW - Quinolines/chemistry
KW - Saccharomyces cerevisiae/enzymology
KW - Sulfanilic Acids/chemistry
KW - Ubiquitins/antagonists & inhibitors
U2 - 10.1016/j.str.2017.10.007
DO - 10.1016/j.str.2017.10.007
M3 - Article
C2 - 29153505
SN - 0969-2126
VL - 25
SP - 1839-1855.e11
JO - Structure
JF - Structure
IS - 12
ER -
