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Development of native ion mobility mass spectrometry methods to study PROTAC systems


Department of Pure and Applied Chemistry

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Dr Rebecca Beveridge No more applications being accepted

About the Project

Small molecule inhibitors have traditionally been developed to bind to a specific protein, thereby preventing it from carrying out its function in the cell. In recent biotechnological approaches, molecules have been created that degrade a target protein, rather than inhibit it. Major advantages of protein degraders over inhibitors are the longer-lasting effects of degraders and the lower concentrations required to achieve efficacy. Moreover, degraders are applicable to a wider spectrum of proteins since binding is not limited to a specific active site. The most popular type of degraders to date are called proteolysis targeting chimeras (PROTACs), which are bifunctional ligands that bind simultaneously to the targeted protein and an E3 ligase, bringing the proteins into a complex, so that the E3 ligase labels the targeted protein for degradation by the cell. PROTACs have been developed against a variety of medically relevant proteins, such as the tumorigenic Androgen Receptor and Estrogen Receptor, as explored in clinical trials.

A current limitation in the development of novel PROTACs is the ability to directly measure the formation of three-component complexes in a fast and efficient manner. Native mass spectrometry (nMS) is an efficient method for analysing the species present in complex mixtures involving E3 ligases, PROTACs, and substrate proteins. This is due to its ability to report on multiple binding stoichiometries present in dynamic protein mixtures, including species populated to a low extent. When coupled with ion mobility, which is a complementary gas-phase technique, different conformations of proteins or protein complexes can also be separated.

The aim of this PhD project is to further develop native ion mobility mass spectrometry methods for the analysis of PROTACs and other protein degraders, which have strong potential as therapies for cancer and other diseases.

We are looking for a motivated candidate, preferably with experience in protein chemistry and/ or mass spectrometry, to join Dr Rebecca Beveridge and Prof. Glenn Burley in the department of Pure and Applied Chemistry at the University of Strathclyde. To apply please send your C.V., a cover letter and details of two referees to [Email Address Removed]. The cover letter should outline why you’re interested in this project and describe your relevant experience.

Funding Notes

Funding is available to cover tuition fees for Home UK or EU applicants for 3 years (from 1st of October 2020), as well as paying a stipend at the Research Council rate (estimated £15,285).

References

Beveridge, Rebecca, et al. "Native mass spectrometry can effectively predict PROTAC efficacy." bioRxiv (2019): 851980.

Tinworth, Christopher P., et al. "PROTAC-mediated degradation of Bruton’s tyrosine kinase is inhibited by covalent binding." ACS chemical biology 14.3 (2019): 342-347.

Hanzl, Alexander, and Georg E. Winter. "Targeted protein degradation: current and future challenges." Current Opinion in Chemical Biology 56 (2020): 35-41.

Sharon, M. and C.V. Robinson, The Role of Mass Spectrometry in Structure Elucidation of Dynamic Protein Complexes. Annual Review of Biochemistry, 2007. 76(1): p. 167-193.

Roy, M.J., S. Winkler, S.J. Hughes, C. Whitworth, M. Galant, W. Farnaby, K. Rumpel and A. Ciulli, SPR-Measured Dissociation Kinetics of PROTAC Ternary Complexes Influence Target Degradation Rate. ACS Chemical Biology, 2019. 14(3): p. 361-368.

Beveridge, Rebecca, et al. "Mass spectrometry locates local and allosteric conformational changes that occur on cofactor binding." Nature communications 7.1 (2016): 1-9.
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