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A strategy for modulation of enzymes in the ubiquitin system.

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.

Pubmed ID: 23287719


  • Ernst A
  • Avvakumov G
  • Tong J
  • Fan Y
  • Zhao Y
  • Alberts P
  • Persaud A
  • Walker JR
  • Neculai AM
  • Neculai D
  • Vorobyov A
  • Garg P
  • Beatty L
  • Chan PK
  • Juang YC
  • Landry MC
  • Yeh C
  • Zeqiraj E
  • Karamboulas K
  • Allali-Hassani A
  • Vedadi M
  • Tyers M
  • Moffat J
  • Sicheri F
  • Pelletier L
  • Durocher D
  • Raught B
  • Rotin D
  • Yang J
  • Moran MF
  • Dhe-Paganon S
  • Sidhu SS


Science (New York, N.Y.)

Publication Data

February 1, 2013

Associated Grants

  • Agency: Wellcome Trust, Id: 092076
  • Agency: Wellcome Trust, Id: 092381
  • Agency: Canadian Institutes of Health Research, Id: 1R01NS072420-01
  • Agency: Canadian Institutes of Health Research, Id: MOP-102536
  • Agency: Canadian Institutes of Health Research, Id: MOP-111149
  • Agency: Canadian Institutes of Health Research, Id: MOP-13494
  • Agency: Canadian Institutes of Health Research, Id: MOP-57795
  • Agency: NINDS NIH HHS, Id: R01 NS072420

Mesh Terms

  • Amino Acid Sequence
  • Combinatorial Chemistry Techniques
  • Conserved Sequence
  • Drug Design
  • Endopeptidases
  • HEK293 Cells
  • Humans
  • Molecular Sequence Data
  • Protease Inhibitors
  • Protein Conformation
  • Protein Structure, Secondary
  • Small Molecule Libraries
  • Ubiquitin
  • Ubiquitin Thiolesterase
  • Ubiquitin-Conjugating Enzymes
  • Ubiquitin-Protein Ligases
  • Ubiquitination