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Probing Conformational Change in Protein Kinases Using Single Molecule Fluorescence Spectroscopy and Unnatural Amino Acids

University of Bath - Pharmacy and Pharmacology

Qualification Type: PhD
Location: Bath
Funding for: UK Students, EU Students
Funding amount: £14,777 UKRI annual stipend (2018/19 rate) + tuition fees + training support grant
Hours: Full Time
Placed On: 12th November 2018
Closes: 16th December 2018

Lead supervisor: Dr Charlotte Dodson

Project enquiries: c.a.dodson@bath.ac.uk

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 [1]. Our assay opens the door to a new class of mechanism-of-action studies for kinase inhibitors by determining the extent of conformational change, whether this is driven by kinase inhibitors, and how it depends on inhibitor chemistry. This is important because incorporating mechanistic information into structure-based drug design at an early stage is expected to reduce expensive late stage failure in clinical trials. Modified kinase dynamics may also provide a mechanism by which otherwise unexplained drug-resistant kinase mutations arising in patients bring about their effects.

The successful candidate will use an expanded genetic code [2] to incorporate unnatural amino acids into the protein kinase c-Met, a cancer target with two FDA-approved inhibitors for lung cancer. This innovation increases the generality of the assay since it removes the need for multiple surface cysteine mutations. She/he will label her/his protein with bright single molecule fluorescent dyes and use this to characterise the in vitro dynamic behaviour of both wildtype protein and clinically arising mutants alone and with ligands (inhibitors and physiological ligands). The results of these single molecule experiments will be used to model the mechanism of inhibitor action and to determine the effect of clinically arising resistance mutations on the dynamics of a protein kinase for the first time.

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

Applicants should hold, or expect to receive, a First Class or high Upper Second Class UK Honours degree (or the equivalent qualification gained outside the UK) in a relevant subject. A master’s level qualification would also be advantageous.

Funding:

Candidates may be considered for a University Research Studentship which will cover UK/EU tuition fees, a training support fee of £1,000 per annum and a tax-free maintenance allowance at the UKRI Doctoral Stipend rate (£14,777 in 2018-19) for a period of up to 3.5 years.

Applications:

Formal applications should be made via the University of Bath’s online application form:

https://samis.bath.ac.uk/urd/sits.urd/run/siw_ipp_lgn.login?process=siw_ipp_app&code1=RDUPA-FP01&code2=0013

Please ensure that your quote the supervisor’s name and project title in the ‘Your research interests’ section.

More information about applying for a PhD at Bath may be found here:

http://www.bath.ac.uk/guides/how-to-apply-for-doctoral-study/

Anticipated start date: 30 September 2019 

References:

[1] Gilburt, J. A. H. et al. (2017). Angew Chem Int Ed Engl 56, 11409-11414. 
[2] Lang, K. et al. (2014). Chem Rev 114, 4764-806. 

   
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