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The structural dynamics of botulinum neurotoxins, Biosciences – PhD (Funded)


About This PhD Project

Project Description

The University of Exeter’s College of Life and Environmental Sciences, in partnership with Ipsen, is inviting applications for a fully-funded PhD studentship to commence in September 2019 or as soon as possible thereafter. For eligible students the studentship will cover UK/EU tuition fees plus an annual tax-free stipend of at least £17,009 for 4 years full-time, or pro rata for part-time study. The student would be based in The Living Systems Institute in the College of Life and Environmental Sciences at the Streatham Campus in Exeter.

Project Description:
Clostridium botulinum toxins (BoNTs) are the most toxic substances known to mankind and exposure can cause fatal neuromuscular paralysis (botulism). However, given at a suitable dose, BoNTs are highly effective medicines for a diverse range of diseases, including spasticity and musculoskeletal conditions. BoNTs are large, multi-functional proteins that must achieve endocytosis into the motor neuron, release into the cytosol, binding to and enzymatic digestion of substrate, ultimately blocking neurotransmission. These functions are dependent on dynamic changes in its structure that relate to protein stability, a key property for biopharmaceuticals. This project will investigate the linkage between the enzyme dynamics, bio/medical function and drug stability. The aims are to (i) understand the molecular mechanisms of infection, (ii) support the safe and effective development of BoNT therapeutics and (iii) differentiate modes of action of different BoNT serotypes.
This project is an opportunity to develop and apply advanced biophysical methods to determine the structural dynamics and stability of large proteins – including hydrogen/deuterium-exchange mass spectrometry, single-molecule optical spectroscopy and protein structural modelling. This studentship provides an exciting opportunity to study the structure and dynamics of botulinum toxins relating to both Clostridium botulinum neurotoxicity and to the development of next generation therapeutics.

[1] M. Kish, et al., bioRxiv.org 2019, 10.1101/654665
[2] E. Kim et al., Vollmer, Science Advances 2017, 3, e1603044
[3] C. L. Dobson et al., Scientific Reports 2016, 6, 38644.
[4] T. Klein et al., Nature Communications 2015, 6, 7877.

This award provides annual funding to cover UK/EU tuition fees and a tax-free stipend. For students who pay UK/EU tuition fees the award will cover the tuition fees in full, plus at least £17,009 per year tax-free stipend. Students who pay international tuition fees are eligible to apply, but should note that the award will only provide payment for part of the international tuition fee and no stipend.

The studentship will be awarded on the basis of merit for 4 years of full-time study to commence in September 2019.

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