This sandwich placement will be based in the lab of Katrin Rittinger.

Project summary

Protein ubiquitination is a post-translational modification that regulates almost every cellular process including protein degradation, DNA repair, signalling processes and host immune responses. Dysregulation of the ubiquitin system is associated with a wide range of diseases including cancer, neurodegeneration, and immune disorders. Furthermore, pathogenic bacteria have evolved ways to hijack the host ubiquitin system, using it to their own advantage to dampen the immune response and promote bacterial survival and proliferation.

We are studying the structure and mechanism of a specific family of bacterial E3 ligases that are structurally distinct from their human counterparts, making them attractive targets for the development of novel antibacterial therapeutics. We would like to complement our existing work with the design of protein binders that may inhibit these enzymes or modulate their function in a manner that would be beneficial for the host.

The project will involve employing established open-source computational protein design tools, such as RFdiffusion, and subsequent production of the recombinant proteins.

To allow the student to gain experience in protein production and characterisation methods, promising binders will be produced and tested in biochemical assays for their effect on substrate ubiquitination and further characterised by biophysical methods such as biolayer interferometry (BLI), Isothermal titration calorimetry (ITC) or other for their interaction with the E3 ligase under investigation. Depending on progress, novel binders, that modulate the activity of bacterial E3 ligases, will be structurally characterised in complex with the relevant E3 protein and their physiological effect analysed by cellular assays.

Candidate background