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Using a combined computational/experimental approach to understand G protein-coupled receptor activation - Reference: MIBTP_Simms_G Protein


College of Life & Health Sciences

About the Project

Applications are invited for four year Postgraduate studentships, supported by the Midlands Integrative Biosciences Training Partnership (MIBTP) (URL: https://warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/structural_biology/activation) and Biotechnology and Biological Sciences Research Council (BBSRC) (URL: https://bbsrc.ukri.org/). Up to 6 studentships are available.

The studentships are available to start in October 2021.

Background to the Studentship

MIBTP scholars join a programme of skills training in year 1. Applicants are required to select an area of study (URL: https://warwick.ac.uk/fac/cross_fac/mibtp/areas_of_research/), but may join the programme with or without selecting a preferred project. The skills training programme includes short rotation projects and students are able to choose a PhD project once they have experienced these differing research environments.
Potential PhD projects are provided to give applicants an idea of the breadth of research within MIBTP and specific research topics at Aston University. You can browse the other projects available here (URL: https://www.findaphd.com/phds/program/midlands-integrative-biosciences-training-partnership-mibtp-funded-phd-studentships/?i369p1045). Additional projects will become available during Year 1 and students can work with potential supervisors during their first year to develop a particular project.

There is an urgent need to develop new methods of drug discovery against novel targets. Computational biology may offer a new direction for drug discovery and recent advances in the field have resulted in new tools to assist in drug discovery campaigns. However, a major bottle neck in the computational design of drugs is the lack of structural information related to protein dynamics. This is especially true for membrane proteins which are currently the largest class of drug targets but have a limited amount of structural information compared with their soluble protein cousins. A further layer of complexity is also added when the lipid bilayer is taken into consideration.

The lipid bilayer not only provides a suitable environment for membrane protein function but individual lipids, which can vary not only between cells but also in disease states, act as allosteric modulators which fine tune the pathways to activation.

The project builds upon a novel computational approach which has identified structural intermediates in the activation of G protein coupled receptors (GPCRs). The method has predicted novel, cryptic binding sites in the intermediate conformations that are not observed in the existing crystallographic structures. The novel binding sites may provide new routes for drug discovery. In addition, investigation of the intermediate structures may also provide predictions of ligand efficacy which is currently unsolved using computational biology.

The aim of this multidisciplinary project is to develop a structural understanding of GPCR activation and will use the human Glucagon Like Protein 1 Receptor (huGLP1R) as a model system. The huGLP1R is currently used as a therapeutic target for the treatment of type 2 diabetes and recent evidence has also implicated its ligands of this protein in neuroprotection against degenerative diseases such as Alzheimer’s. The identification of small molecules which bind to this class of membrane proteins would be of enormous benefit in several areas. This is a multidisciplinary project in which the student will have extensive training in a range of molecular, pharmacological, protein expression and computational techniques to provide a rounded view of an exciting area of drug discovery.

Person Specification

The successful applicant should have been awarded, or expect to achieve, a Masters degree in a relevant subject with a 60% or higher weighted average, and/or a First or Upper Second Class Honours degree (or an equivalent qualification from an overseas institution) in a relevant subject. Full entry requirements for Aston University can be found on our website (URL: https://www.aston.ac.uk/study/courses/phd-life-and-health-sciences).

Full entry requirements for MIBTP can be found on their website (URL: https://warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/application/#Eligibility).

Contact information

For further information on the advertised project, contact Dr John Simms at

Submitting an application

Details of how to apply for the studentship can be found here (URL: https://jobs.aston.ac.uk/Vacancy.aspx?ref=R200317).

If you require further information about the application process contact the Postgraduate Admissions team


Funding Notes

The studentships include a fee bursary to cover the Home fees rate, plus a tax free stipend of at least £15,285 p.a (to rise in line with UKRI recommendation).

Overseas Applicants
Overseas applicants may apply for this studentship, and the home fees rate will be covered. UKRI funding will not cover the difference between UK tuition fees and international tuition fees; international tuition fee payers will be required to fund the fee difference themselves. MIBTP encourages international students with existing sources of funding (e.g. fellowships) to apply. The difference between home and international fees is £13,443 in 2020/21. Please confirm in your application how you will fund the fee difference.

References

Orellana, L. (2019). Large-Scale Conformational Changes and Protein Function: Breaking the in silico Barrier. Frontiers in Molecular Biosciences. 6.
Simms, J et al (2018). Photoaffinity cross-linking and unnatural amino acid mutagenesis reveal insights into calcitonin gene-related peptide binding to the calcitonin receptor-like


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