Structural biology tools to investigate and target ubiquitin system proteases in cancer

Ubiquitination targets proteins for degradation and regulates virtually all cellular signalling pathways in eukaryotes. The human genome encodes over 50 ubiquitin specific proteases (USPs) that cleave ubiquitin from modified proteins to salvage them from proteasomal degradation. USPs have key roles in cell cycle progression, DNA damage repair and gene regulation and thus USP inhibition is a promising strategy for developing novel treatments for cancer, chronic inflammation, and neurodegenerative diseases. 

This exciting project will build on our longstanding interests and expertise in the area. We aim to advance the molecular understanding of the structure, function and specificity of a USP by trapping substrates and studying key binding interactions. Despite their importance, how these cysteine proteases specifically recognise their target substrates and thus exert their regulatory function in health and disease is poorly understood and hampers inhibitor discovery.

We will use protein engineering to generate USP substrates relevant to cancer biology and produce molecular complexes for structure determination by state-o-the-art single particle cryo-electron microscopy or X-ray crystallography in combination with complementary biochemical techniques. This will allow us to identify binding pockets and key residues critical to the USP’s function that can be verified by mutagenesis and functional assays in view of using this information for the design of specific inhibitors.

The project transcends disciplinary boundaries and will be led by a supervisory team reflecting the unique strengths of the Biomolecular Science and Medicinal Chemistry Division in the School of Pharmacy (https://www.nottingham.ac.uk/pharmacy/research/divisions/biomolecular-science-and-medicinal-chemistry/index.aspx.).

You will be trained in bioinformatics, protein engineering, structural biology and biochemical assays. Opportunities also exist to learn other techniques depending on the interests of the applicant. You will be a member of the vibrant School of Pharmacy postgraduate community benefiting from a diverse and stimulating research environment. The PhD programme will equip you with highly sought-after multidisciplinary skills in the biomedical research area. Please contact ingrid.dreveny@nottingham.ac.uk for any informal enquiries. We will be happy to answer questions from interested applicants and provide more information.