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Understanding Movement and Mechanism in Molecuar Machines (MACMILLANFU18SF)

Project Description

This PhD project offers a multidisciplinary research environment including training in magnetic resonance and molecular dynamics. We study the architecture and functional dynamics of membrane proteins, many medically relevant. Special interest is on large multi-subunit complexes such as transporter systems and their interaction with intra-cellular signalling pathways. There is increasing evidence that membrane proteins do not act alone, but that they are organised as nano-machineries which function through the concerted action of individual components with high precision and specificity observed in both time and space.

We are seeking to unravel the principles underlying the architecture and dynamics of these protein nano-machineries as well as their function and regulation. Our experimental approach focuses on the use of magnetic resonance spectroscopies in combination with advanced molecular dynamics techniques (MD) to underpin the experimental observations to provide a dynamic description of function.

This project addresses the important theme of transport across biological membrane through the study of a specific amino acid transporter LeuT which is a member of the SLC6 transporter family, a structural homologue of the human neurotransmitter transporters implicated in several diseased states including depression, anxiety and attention-deficit hyperactivity disorder. Recent static crystal structures have suggested large scale conformational changes and we aim to probe the functional dynamics of the protein using a combination of state-of-the-art magnetic resonance techniques and molecular dynamics simulations.

Start Date: October 2018
Mode of Study: Full time
Application deadline: 31 May 2018, please note applications are processed as soon as they are received and the project may be filled before the closing date, so early application is encouraged.

Funding Notes

This PhD project is offered on a self-funding basis. It is open to applicants with funding or those applying to funding sources. Details of tuition fees can be found at View Website.

A bench fee is also payable on top of the tuition fee to cover specialist equipment or laboratory costs required for the research. The amount charged annually will vary considerably depending on the nature of the project and applicants should contact the primary supervisor for further information about the fee associated with the project.

Acceptable fist degree: Chemistry, Biochemsitry, Biophysics, Physics or related at 2:1


i) Jenny Hall, Azmat Sohail, Thomas Stockner, Harald H. Sitte, Jesus Angulo, & Fraser MacMillan Saturation Transfer Difference NMR on an Integral Membrane Transport Protein: Determination of Substrate Binding Affinity, J. Am. Chem. Soc submitted (2018)
ii) John Anderson, Daniel Watkins, Jonathan Jenkins, Katie Grayson, Nicola Wood, Jack Steventon, Kristian Le Vay, Matt Goodwin, Anna Mullen, Henry Bailey, Matthew Crump, Fraser MacMillan, Adrian Mulholland, Gus Cameron, Richard Sessions, and Stephen Mann Construction and in vivo assembly of a catalytically proficient and hyperthermostable de novo enzyme Nature Communications 8, 354 (2017)
iii) A Mullen, J Hall, J Diegel, I Hassan, A Fey, F MacMillan, Membrane transporters studied by EPR spectroscopy: structure determination and elucidation of functional dynamics Biochemical Society Transactions 44, 905-915 (2016)
iv) E. Deplazes, S.L. Begg SL, J. H. van Wonderen, R. Campbell, B. Kobe, J.C. Paton, F. MacMillan, C. A. McDevitt, M. L. O'Mara “Characterizing the conformational dynamics of metal-free PsaA using molecular dynamics simulations and electron paramagnetic resonance spectroscopy.” Biophys Chem. 207, 51-60 (2015)

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