The covalent attachment of the small protein ubiquitin to substrates regulates virtually all cellular processes, and its modulation with small molecules is poised to revolutionise modern medicine. Central to the ubiquitin system are E3 ligase enzymes, which catalyse the covalent transfer of ubiquitin to specific substrates.

Our multidisciplinary lab has developed pioneering technologies for E3 ligase discovery and activity measurement ^1,2. Using these approaches, we have identified several E3 ligases with unconventional transfer and regulatory mechanisms ^2-5. For example, MYCBP2, a member of the RING-Cys-relay (RCR) subtype, is a central regulator of neuronal integrity ^2,3. We have also characterised RNF213-ZNFX1 (RZ-type) E3 ligases, which confer innate restriction to microbial pathogens. Their distinct ubiquitin transfer mechanisms and remarkable regulatory interplay with nucleotide- and nucleic acid–binding domains unlocks novel ways of therapeutically modulating E3 activity.

Key to advancing both our understanding of these mechanisms and the development of new therapies is the atomic-level characterisation of their molecular functions. Equally crucial is developing new technologies for interrogating E3 activity in cells.

We offer PhD projects that will:

• Use cryo-EM and X-ray crystallography to determine structures of pivotal catalytic intermediates.
• Develop chemical biology tools to provide enhanced insights into E3 ligase activity in cells.
• Explore how rewiring the ubiquitin system might serve as a strategy to treat disease.

References

1.Pao, K.-C. et al. Probes of ubiquitin E3 ligases enable systematic dissection of parkin activation. Nature Chemical Biology 12, 324–331 (2016).

2. Pao, K.-C. et al. Activity-based E3 ligase profiling uncovers an E3 ligase with esterification activity. Nature 556, 381–385 (2018).

3.Mabbitt, P. D. et al. Structural basis for RING-Cys-Relay E3 ligase activity and its role in axon integrity. Nat Chem Biol 16, 1227–1236 (2020).

4.Barnsby-Greer, L. et al. UBE2A and UBE2B are recruited by an atypical E3 ligase module in UBR4. Nat. Struct. Mol. Biol. 31, 351–363 (2024).

5.Ahel, J. et al. ATP functions as a pathogen-associated molecular pattern to activate the E3 ubiquitin ligase RNF213. Nat. Commun. 16, 4414 (2025).