Structural Basis for the Inhibitory Effects of Ubistatins in the Ubiquitin-Proteasome Pathway

Mark A Nakasone, Timothy A Lewis, Olivier Walker, Anita Thakur, Wissam Mansour, Carlos A Castañeda, Jennifer L Goeckeler-Fried, Frank Parlati, Tsui-Fen Chou, Ortal Hayat, Daoning Zhang, Christina M Camara, Steven M Bonn, Urszula K Nowicka, Susan Krueger, Michael H Glickman, Jeffrey L Brodsky, Raymond J Deshaies, David Fushman (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1839-1855.e11
Number of pages29
JournalStructure
Volume25
Issue number12
Early online date16 Nov 2017
DOIs
Publication statusPublished - 5 Dec 2017

Keywords

  • Binding Sites
  • Cell Line
  • HeLa Cells
  • Humans
  • Molecular Docking Simulation
  • Proteasome Endopeptidase Complex/chemistry
  • Protein Binding
  • Quinolines/chemistry
  • Saccharomyces cerevisiae/enzymology
  • Sulfanilic Acids/chemistry
  • Ubiquitins/antagonists & inhibitors

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