Projects per year
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.
|Number of pages||13|
|Journal||Journal of Molecular Biology|
|Early online date||3 Mar 2022|
|Publication status||Published - 30 Apr 2022|
- genetic code expansion
- non-canonical amino acid
- E2 ubiquitin-conjugating enzymes
- bioorthogonal reaction
FingerprintDive into the research topics of 'Selective Inhibition of Cysteine-Dependent Enzymes by Bioorthogonal Tethering'. Together they form a unique fingerprint.
- 1 Finished
Activity Based Proteomics of E3 Ligases
Biotechnology and Biological Sciences Research Council
1/07/17 → 30/06/21