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FindA University Ltd Featured PhD Programmes

Using single molecule spectroscopy to determine the drivers of conformational change in protein kinases


Project Description

Protein kinases are central to many cellular processes (eg cell division and the response to external signals) and are current drug targets in cancer, cardiac and inflammatory disease. The conformation of a protein kinase underlies its catalytic activity and is thought to be crucial to inhibitor binding. However, to date, measuring changes in kinase conformation in solution and determining the factors driving this process has proved almost impossible because interconversion occurs on the same timescale as NMR intermediate exchange.

Very recently, the Dodson laboratory has developed a single molecule fluorescence assay that is capable of monitoring kinase interconversion in solution for the first time. This has enabled us to show that phosphorylated kinase is dynamic in solution and to determine new information about the way in which kinase inhibitors bind to their targets [1,2]. Our assay also opens the door to directly testing hypotheses about which kinase residues drive conformational change.

The successful candidate for this PhD will investigate the role of a highly conserved triplet of amino acids (the DFG motif) in the dynamics of a regulatory region known as the kinase activation loop. She/he will use our technology to determine the factors which control the rate of conformational interconversion and the role of dynamics in kinase catalysis.

This project is highly interdisciplinary and is part of a growing interest in conformational change in drug-target interactions. It is suitable for candidates with either a biological or physical science background.

References

1. Gilburt, J. A. H. et al. (2017). Angew Chem Int Ed Engl 56, 11409-11414.
2. Gilburt, J. A. H. et al. (2019). Chem Sci 10(14), 4069-4076

How good is research at University of Bath in Allied Health Professions, Dentistry, Nursing and Pharmacy?

FTE Category A staff submitted: 54.20

Research output data provided by the Research Excellence Framework (REF)

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