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.
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
Amino Acid Sequence
Combinatorial Chemistry Techniques
Molecular Sequence Data
Protein Structure, Secondary
Small Molecule Libraries
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