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Active-site directed probes are powerful in studies of enzymatic function. We report an active-site directed probe based on a warhead so far considered unreactive. By replacing the C-terminal carboxylate of ubiquitin (Ub) with an alkyne functionality, a selective reaction with the active-site cysteine residue of de-ubiquitinating enzymes was observed. The resulting product was shown to be a quaternary vinyl thioether, as determined by X-ray crystallography. Proteomic analysis of proteins bound to an immobilized Ub alkyne probe confirmed the selectivity toward de-ubiquitinating enzymes. The observed reactivity is not just restricted to propargylated Ub, as highlighted by the selective reaction between caspase-1 (interleukin converting enzyme) and a propargylated peptide derived from IL-1β, a caspase-1 substrate.


Reggy Ekkebus, Sander I van Kasteren, Yogesh Kulathu, Arjen Scholten, Ilana Berlin, Paul P Geurink, Annemieke de Jong, Soenita Goerdayal, Jacques Neefjes, Albert J R Heck, David Komander, Huib Ovaa. On terminal alkynes that can react with active-site cysteine nucleophiles in proteases. Journal of the American Chemical Society. 2013 Feb 27;135(8):2867-70

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PMID: 23387960

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