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Abstract
A general approach for the rapid and selective inhibition of enzymes in cells using a common tool compound would be of great value for research and therapeutic development. We previously reported a chemogenetic strategy that addresses this challenge for kinases, relying on bioorthogonal tethering of a pan inhibitor to a target kinase through a genetically encoded non-canonical amino acid. However, pan inhibitors are not available for many enzyme classes. Here, we expand the scope of the chemogenetic strategy to cysteine-dependent enzymes by bioorthogonal tethering of electrophilic warheads. For proof of concept, selective inhibition of two E2 ubiquitin-conjugating enzymes, UBE2L3 and UBE2D1, was demonstrated in biochemical assays. Further development and optimization of this approach should enable its use in cells as well as with other cysteine-dependent enzymes, facilitating the investigation of their cellular function and validation as therapeutic targets.
Original language | English |
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Article number | 167524 |
Number of pages | 13 |
Journal | Journal of Molecular Biology |
Volume | 434 |
Issue number | 8 |
Early online date | 3 Mar 2022 |
DOIs | |
Publication status | Published - 30 Apr 2022 |
Keywords
- genetic code expansion
- non-canonical amino acid
- chemogenetics
- E2 ubiquitin-conjugating enzymes
- bioorthogonal reaction
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Dive into the research topics of 'Selective Inhibition of Cysteine-Dependent Enzymes by Bioorthogonal Tethering'. Together they form a unique fingerprint.Projects
- 1 Finished
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Activity Based Proteomics of E3 Ligases
Virdee, S. (Investigator)
Biotechnology and Biological Sciences Research Council
1/07/17 → 30/06/21
Project: Research