Deubiquitinase structure determination for developing novel therapeutics

About the Project

Rational drug design relies on the availability of detailed structure information and the molecular properties of key binding sites that can be targeted by small molecular inhibitors or biologics. With the emergence of artificial intelligence structure prediction methods (AlphaFold) and key advances in cryo-electron microscopy and X-ray crystallography, we have access to unprecedented tools to facilitate rational drug design.

In this exciting project, we will make use of these advanced techniques toolkit to characterise the structure and substrate interactions of a ubiquitin specific protease (USP) for drug design. 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. 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 selective inhibitor discovery.

The lab has longstanding interests and expertise in the area and recently developed a novel deubiquitinase assay. We will build on this expertise and 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.

Funding Notes

This project is for sponsored or self-funded home/EU or international students who can cover their own fees and living expenses. If you are a student who wishes to apply for your own funding, please get in touch about how this can be supported and also see Postgraduate study - The University of Nottingham for information. Targeted funding opportunities may exist for applicants with home fee status.

References

Zhang J, Allen J, Ward SJ, Dekker LV, Dreveny I. A versatile fluorescence polarization-based deubiquitination assay using an isopeptide bond substrate mimetic (IsoMim). J Biol Chem. 2025 Jun 6;301(7):110342. doi: 10.1016/j.jbc.2025.110342.

Maurer SK, Mayer MP, Ward SJ, Boudjema S, Halawa M, Zhang J, Caulton SG, Emsley J, Dreveny I. (2023) Ubiquitin-specific protease 11 structure in complex with an engineered substrate mimetic reveals a molecular feature for deubiquitination selectivity. J Biol Chem. 299(11):105300. doi: 10.1016/j.jbc.2023.105300.

Lange SM, Armstrong LA, Kulathu Y (2022) Deubiquitinases: From mechanisms to their inhibition by small molecules, Mol. Cell 82(1), 15-29, doi: 10.1016/j.molcel.2021.10.027.