Ubiquitin E3 ligases are central regulators of cellular proteostasis and are directly implicated in cancer, neurodegeneration, and immune-related pathologies. A detailed understanding of their molecular and structural mechanisms is essential for therapeutic development.

Using E3 activity-based chemical probes, we have substantially expanded the known landscape of E3 ligase subtypes-effectively doubling the number previously recognized. Notably, we have identified and characterized novel classes, including Ring-Cys-Relay (RCR) 1,2, hemiRING 3, and RNF213/ZNFX1 (RZ) 4, which play critical roles in cancer progression, axonal maintenance, and innate immune signaling.

We are seeking a highly motivated postdoctoral researcher to join the Satpal Virdee Lab for a 3-year project further exploring the molecular and structural mechanisms of these recently discovered atypical E3 ligases. These ligases play crucial roles in immune responses and axonal integrity, requiring tightly coordinated regulation-yet how this is achieved remains unclear.

These atypical ligases also exhibit activity toward non-lysine substrates, making them highly unusual. How they conjugate ubiquitin to these atypical substrates-and how the resulting ubiquitin signals are recognized-is not fully understood. Central to uncovering their cellular functions is determining where in the cell they are active, a question that demands the development of new technologies which our lab is well-positioned to pursue.

This project will use chemical biology, proteomics, and structural biology to:

• Gain insights into the molecular basis for atypical E3 ligase activation
• Characterize the polyubiquitin architectures assembled and identify their downstream effectors
• Develop novel E3 ligase activity-based imaging technologies

This position offers a unique opportunity to make fundamental discoveries with therapeutic implications in infection, cancer, and cerebrovascular disease. Ideal candidates will have expertise in biochemistry, structural biology, or chemical biology, and a passion for uncovering molecular mechanisms.

1. Pao et al. Activity-based E3 ligase profiling uncovers an E3 ligase with esterification activity. (2018) Nature 556, 381-385, doi:10.1038/s41586-018-0026-1
2. Mabbitt et al. Structural basis for RING-Cys-Relay E3 ligase activity and its role in axon integrity. (2020) Nat Chem Biol. 16(11):1227-1236, doi: 10.1038/s41589-020-0598-6
3. Barnsby-Greer et al. UBE2A and UBE2B are recruited by an atypical E3 ligase module in UBR4. (2024) Nat Struct Mol Biol, 31, 351-363, doi: 10.1038/s41594-023-01192-4
4. Ahel et al. ATP functions as a pathogen-associated molecular pattern to activate the E3 ubiquitin ligase RNF213. (2025) Nat Commun 16(1):4414. doi: 10.1038/s41467-025-59444-4

MRC Protein Phosphorylation and Ubiquitylation Unit (MRC PPU):

The MRC PPU is one of the world's most renowned centres for research on protein phosphorylation and ubiquitylation (http://www.ppu.mrc.ac.uk/). Many world-leading researchers in the field of signal transduction have trained within the MRC PPU. The major aims of the MRC PPU are to advance understanding of the role of protein phosphorylation and ubiquitylation in cell regulation and human disease, to facilitate the development of drugs to treat diseases caused by abnormalities in phosphorylation, to generate reagents and improve technologies. A key remit of the MRC PPU is to train the next generation of scientists who will advance our understanding in this crucial area of medical research.

School of Life Sciences (SLS):

The MRC PPU is based within the School of Life Sciences at the University of Dundee, a world-class academic institution with a reputation for the excellence of its research, its high-quality teaching and student experience, and the strong impact of its activities outside academia. With 900 staff from over 60 countries worldwide the School provides a dynamic, multi-national, collegiate and diverse environment with state-of-the-art laboratory, technology and teaching facilities.

Division of Signal Transduction Unit (DSTT):

The Division of Signal Transduction Therapy (DSTT) was established in 1998. This division operates as a unique collaboration between scientists in the MRC PPU and signalling researchers at the University of Dundee's School of Life Sciences and the pharmaceutical industry. The DSTT is widely regarded as a model for how academia should interact with industry. The DSTT operates as a simple bridging mechanism to enable our PIs working on ubiquitylation and phosphorylation to effectively interact with major pharmaceutical companies to help accelerate the early stages of drug discovery.

Your priorities will include:

• Design and implementation of biochemical enzyme assays
• Molecular biology-based molecule cloning and construct design
• Protein structure determination by crystallography or cryoEM
• Development of novel chemical biology research tools
• Maintenance of lab records comprehensive

Who we're looking for:

• Experience with the ubiquitin system
• Experience with biochemistry and cell culture methods
• Excellent communication skills
• Experience with biophysical techniques
• Experience with probe-based technologies for enzyme study

We are one of the UK's leading universities, internationally recognised for our expertise across a range of disciplines and research breakthroughs in multiple areas, including science, medicine and engineering, amongst many others. Our purpose is to transform lives, locally and globally, which we do as a community of staff (Professional Services and academic Schools), students and alumni. Professional Services directorates are key to delivering the University strategy and driving change across the University.

For further information about this position please contact Satpal Virdee (s.s.virdee@dundee.ac.uk). To find out more about MRC PPU please visit https://www.ppu.mrc.ac.uk/