Activity probes targeting enzymes in the ubiquitin system.

Abstract:  Protein ubiquitination regulates most aspects of cell life. Ubiquitin is conjugated onto a target protein via a cascade reaction involving the consecutive action of E1, E2 and E3 enzymes. The reverse reaction is executed by deubiquitinating enzymes (DUBs). Many of these enzymes are emerging as promising drug targets, for example in oncology and parasitology. However, developing drugs which are capable of targeting these enzymes requires access to suitable assay reagents and tool compounds, including activity-based probes.  DUB probes have been proving their value for some time now, for example in identifying and validating DUBs as drug targets in trypanosome and leishmania parasites.  Probes targeting the ubiquitin conjugating machinery, however, had been lacking, until now. Exciting novel probes will be presented which allow for the first time to monitor catalysis along the whole E1-E2-E3 orchestrated ubiquitin conjugation pathway.  The approach is easily extended to ubiquitin-like conjugating cascades, as exemplified by the generation of Nedd8 and SUMO probes.  In this presentation the utility of activity-based probes in drug discovery in the ubiquitin field will be discussed, focussing on their use in target validation (activity-based protein profiling, chemical proteomics, monitoring target activity in live cells), crystallography and structure-based drug design.

The host for this seminar is