WEHI Ubiquitin Signalling Special Seminar hosted by Associate Professor Bernhard Lechtenberg

Sonja Lorenz

Group Leader at Max Planck Institute for Multidisciplinary Sciences, Germany

Understanding and manipulating ubiquitin ligase specificity

Davis Auditorium
Join via TEAMS
Including Q&A session

Please note this presentation will not be recorded

Ubiquitination is a central regulator of protein functions in eukaryotes, governing myriad cellular pathways. It is driven by an enzymatic cascade, including over 600 ubiquitin ligases that dynamically modify more than 50.000 sites in the human proteome. Deregulation of this fine-tuned system is tightly linked to human diseases, making ubiquitination enzymes prime targets for therapeutic manipulations. While immunomodulatory drugs and recent advances with proteolysis-targeting chimeras (PROTACs) and molecular glues have illustrated the value of harnessing ubiquitin ligase activities for therapeutic benefit, current clinical strategies target only a handful of RING-type ubiquitin ligases. In the same vein, the development of ubiquitin ligase inhibitors has been challenging, as these enzymes typically lack small-molecule binding pockets at their active sites, and our understanding of regulation mechanisms that may be exploited for allosteric inhibition is still limited. Two lines of basic, mechanistic discoveries by my research group have opened innovative opportunities to overcome these limitations: (i) We uncovered a druggable allosteric regulation mode in an infection-associated E3 from human-pathogenic Leishmania parasites, the causative agents of a major neglected tropical disease. (ii) We found that exogenous drug-like small molecules can serve as substrates of ubiquitin ligases in the cell. In my talk, I will provide an overview of these ongoing projects and their translational implications.

All welcome!