Chemical Biology - Discovery Probes for Ubiquitin-like E3 Ligases

Modification of proteins with ubiquitin-like proteins (Ubls) is a critical cellular process linked to pathogen resistance, cancer, and selective organelle degradation. Central to their conjugation to substrates are E3 ligase enzymes (E3s), yet for many Ubls the E3s are poorly understood or remain completely unknown. The Virdee lab has pioneered the development of activity-based probes (ABPs) for the related ubiquitin system, which has led to several field-changing discoveries (Pao et al., Nat Chem Bio 2016; Pao et al., Nature 2018; Mathur et al., Cell Chem Biol. 2020; Mabbitt et al. Nat Chem Biol. 2020). This project will build upon this expertise and expand its approach to Ubl systems. Ubl E3 ABPs will be constructed using the lab’s modular chemical protein synthesis methods. These powerful tools will then be deployed in combination with proteomics to discover entirely novel E3 ligases. The transformative understanding of these understudied posttranslational modifications will enrich our understanding of the cellular function of these modifiers and could enable the development of new therapeutic targets.

Enthusiastic candidates should ideally have recently carried out a PhD in biochemistry or a chemistry related area. The position will be a fantastic opportunity for candidates to broaden their skillset by working in a multidisciplinary lab using state-of-the-art technologies. Coupled with this exciting area of biological focus, the project will provide an excellent opportunity for career development with mentoring support to reach career aspirations. The successful applicants will join an international team in an exciting and interactive environment, equipped to the very highest standards, and with generous consumable support.

Your priorities will include:

• Carry out chemical protein synthesis of protein-based probe molecules for Ubl E3s
• Perform assays using purified protein and cell extracts
• Preparation of data for manuscript preparation
• Liaise with other lab members and collaborators
• Maintenance of meticulous lab records

Who we’re looking for:

Enthusiastic candidates should ideally have recently carried out a PhD working in structural biology or biochemistry.

• Enthusiasm for technology development working at the chemistry-biology interface
• Experience with chemical biology techniques
• Biochemical experience

This contract is for a fixed term period of 3 years

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 and ubiquitylation, 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 three leading pharmaceutical companies (Boehringer Ingelheim, GlaxoSmithKline, Merck Serono). 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 three major pharmaceutical companies to help accelerate the early stages of drug discovery. The DSTT model enables industrial researchers working in any of the worldwide outlets of three pharmaceutical companies to effectively work with the ~200 Dundee-based researchers that participate in the collaboration to understand the fundamentals of the molecular causes of disease that result from disruptions in protein phosphorylation and ubiquitylation networks.

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. Conveniently located on the banks of River Tay, our main city-centre campus is at the heart of Dundee - an up-and-coming, friendly, compact and affordable city with a rich heritage in design and technology. Just a short walk from the V&A Museum of Design Dundee, we’re close to both the train and bus stations. We also have campuses at Ninewells Hospital and in Kirkcaldy which are easily accessible via local transport links.

For further information about this position please contact Satpal Virdee s.s.virdee@dundee.ac.uk. To find out more about the MRC Protein phosphorylation and ubiquitylation unit please visit https://www.ppu.mrc.ac.uk.