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(BBSRC DTP CASE) In situ structural characterization of membrane proteins for drug development


   Faculty of Biology, Medicine and Health

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  Dr Argyris Politis, Dr C Francavilla  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

This project aims to enable the in situ structural analysis of membrane proteins. Membrane proteins play a crucial role in cellular function and are key drug targets. Understanding how membrane proteins move and function requires insights into both protein and the surrounding environment. In particular, lipids surround membrane proteins and can modulate their structure and function. Detailed knowledge of this modulation remains largely unknown hindering the mechanistic understanding of such drug targets and the development of novel therapeutics. 

Over the past decade, biomolecular mass spectrometry (MS) has emerged as a particularly useful tool for functional characterization of membrane proteins1. Here, we aim to go beyond the state-of-the-art and develop a platform that combines hydrogen deuterium exchange (HDX)-MS with cyclic ion mobility (IM)-MS to link function with dynamics. We have recently shown that lipid-protein interactions regulate functional conformations in secondary transporters2. Here, we target human receptors namely the Receptor Tyrosine Kinase Fibroblast Growth Factor receptor (FGFR) implicated in cancer and genetic disorders (Francavilla O’Brien 2022) and class A G-Protein-Coupled Receptors (GPCRs) implicated in heart disease and mental health. In particular, GPCRs, constitute the target of >30% of all marketed drugs, are tightly regulated by external stimuli and lipid environment; the latter is poorly understood due to the lack of tools. A key aim is to study how cell membranes affect the conformational dynamics, ligand binding and molecular pathways. We aim to translate the technology into a platform for profiling receptor modulators with desired functionality. We will manipulate functional lipids surrounding the proteins and probe both plasticity of receptor conformation and allosteric modulation of their activity. 

Overall, we expect that our approach and platform will be directly transferable to other similar systems allowing interrogation of the functional dynamics implicated to  the wider class of receptors, paving the way for the technique to be used more widely in structure-based drug design. 

Eligibility 

Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.   

Before you Apply 

Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.  

How To Apply 

To be considered for this project you MUST submit a formal online application form - full details on eligibility how to apply can be found on the BBSRC DTP website https://www.bmh.manchester.ac.uk/study/research/bbsrc-dtp/  

Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered.  If you have any queries regarding making an application please contact our admissions team [Email Address Removed]  

Equality, Diversity and Inclusion  

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/  


Funding Notes

This is a 4 year CASE studentship in partnership with Waters Corporation . This scheme is open to both the UK and international applicants. We are only able to offer a limited number of studentships to applicants outside the UK. Therefore, full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

References

Ahdash, Z.; Pyle E.; Allen, W.J.; Corey, R.A.; Collinson, I. Politis, A*. HDX-MS reveals nucleotide-based, anti-correlated opening and closure of SecA and SecY channels of the bacterial translocon. eLife, e47402, 2019
Martens, C.; Shekhar, M.; Lau, A.M.; Tajkhorshid, E., Politis, A*. Integrating hydrogen-deuterium exchange mass spectrometry with molecular dynamics simulations to probe lipid-modulated conformational changes in membrane proteins. Nature Protocols, 14, 3183–3204, 2019
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