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(BBSRC DTP) Understanding Allostery in G Protein-Coupled Receptors (GPCRs) using Electron Paramagnetic Resonance and Lanthanide induced Chemically Induced Dynamic Nuclear Polarization


Department of Chemistry

Manchester United Kingdom Analytical Chemistry Biochemistry Biophysics Computational Chemistry Physical Chemistry Structural Biology

About the Project

This exciting and challenging project provides a unique opportunity for a student interested in a multidisciplinary biosciences project to work across two international campuses, the University of Manchester (UoM) and the University of Toronto (UoT). There will be opportunities to learn many different biophysical, molecular biology and computational techniques, to study the agonist protein-interactions in G protein-coupled receptors (GPCRs).1

Supervision for the 4-year PhD will be led by Dr Bowen (UoM) and Prof. Prosser (UoT). The student will be based at UoM for years 1/4 with an extended research visit to UoT during years 2/3. Year 1 will include three short research projects, with training in Electron Paramagnetic Resonance (EPR), at the UK national facility for EPR, and computational and data analysis techniques including Density Functional Theory (DFT) provided.

The PhD work will focus on the study of G protein-coupled receptors (GPCRs) using the magnetic resonance methods EPR and Lanthanide induced Chemically Induced Dynamic Nuclear Polarization (CIDNP).2,3

GPCRs represent a ubiquitous membrane protein family and are targets for over 25% of all approved drugs. Their diverse signalling pathways are driven by complex pharmacology arising from a conformational ensemble rarely captured by structural methods. EPR and CIDNP are useful for studying this complex system as they are specific to certain chemical moieties that can be introduced into the system at known locations. The Prosser lab is able to prepare large quantities of purified and reconstituted GPCRs in complex with heterotrimeric G proteins with the moieties required for EPR and CIDNP using high-density lipoprotein nanodiscs. Training will be given at UoT.

GPCRs can be stimulated by agonists resulting in measurable hydrolysis and “G protein coupling”. We are interested in studying a well-known, yet poorly understood signalling phenomenon; the allosteric action of divalent cations. Recent studies reveal that sub-milliomolar concentrations of Mg(II), Ca(II), or Mn(II) are needed to establish full efficacy in conjunction with an agonist, and point to a conserved metal binding motif which is reinforced by the agonist, as the associated G protein reaches the nucleotide-free activation intermediate. We propose studying the binding of EPR active Mn(II), measuring the distance between Mn(II) and an artificially introduced nitroxide spin-label in the receptor as a function of different drugs. This will be achieved using EPR Pulsed Dipolar Spectroscopy, specifically Relaxation Induced Dipolar Modulation Enhancement.4 The results will help to identify the binding site of the Mn(II) and confirm our hypotheses regarding allosteric mechanisms.

https://www.research.manchester.ac.uk/portal/alice.bowen.html
https://www.chemistry.manchester.ac.uk/epr/
http://biochemistry.utoronto.ca/person/r-scott-prosser/
https://www.research.manchester.ac.uk/portal/nicholas.chilton.html
http://sites.utm.utoronto.ca/prosserlab/content/research

Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

UK applicants interested in this project should make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).
If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.

Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the BBSRC DTP website http://www.manchester.ac.uk/bbsrcdtpstudentships




Funding Notes

Funding will cover UK tuition fees/stipend only. The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a limited number of scholarships that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

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 View Website

References

1) Nature. 2009, 459(7245), p356–363. doi: 10.1038/nature08144.
2) ChemPlusChem, 2020, 85(2). doi: 10.1002/cplu.201900705
3) J. Am. Chem. Soc. 2011, 133 (21), p8062. doi: 10.1021/ja111613c; Annu. Rev. Biophys. Biomol. Struct. 2002, 31, p275. doi: 10.1146/annurev.biophys.31.101101.140927
4) J. Phys. Chem. A. 2016, 120(20) p3463-72. doi: 10.1021/acs.jpca.6b00716

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