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Investigating functional and structural roles of G-protein coupled receptor oligomerization


Project Description

G-protein coupled receptors (GPCRs) modulate cellular responses to diverse bioactive molecules and drugs. The current model of GPCR signalling incorporates an ever-increasing complexity in these pathways, to which the association of GPCRs as dimers or oligomers either with themselves (homomers) or distinct GPCRs (heteromers) has made a significant contribution. However, the ability to pharmacologically exploit homo- versus hetero-oligomers has been impeded by a lack of high-resolution structural information that underlies the unique function of these homo and heteromeric receptors. This project aims to combine a structural and cellular approach to identify how GPCR-GPCR associations impacts receptor function. We will focus primarily on the adenosine A2AR and its known association with the dopamine D2R to identify specific receptor regions involved in modulating homo and heteromer formation by a combination of molecular, computational, biophysical, cellular and super-resolution microscopy approaches. The ability to promote receptor homomeric and heteromeric association, via receptor mutants and/or the use of nanobodies, will be assessed functionally. Critically this process will also identify stable complexes for structural studies. The insights gained would facilitate identification of unique receptor oligomer-specific targeting sites for structure-based drug discovery.

Key skills

Protein expression, BRET analysis, mutagenesis, protein isolation, stability analysis cryo-EM analysis

Residential & Academic Eligibility

UK or EU nationals who are ordinarily residents of the UK are eligible to apply. Candidates must carefully read Annex 1 of the RCUK Training Grant Guide (https://www.ukri.org/files/legacy/publications/rcuk-training-grant-guide-pdf/) to determine their own eligibility before applying. Candidates are expected to have a BSc degree, in a relevant subject, at 2:1 level or better, as well as a postgraduate Masters qualification, by October 2020. Exceptional students at Bachelor’s level may also be considered.

How to Apply

Please visit our BBSRC DTP webpage to obtain more information on how to apply (https://www.imperial.ac.uk/bbsrc-doctoral-training-partnership/)

Deadline for applications: 12noon on Friday, 21 February 2020.

Funding Notes

The studentships cover: (i) an annual tax-free stipend at the standard Research Council rate (£17,009 for 2019-2020, to be confirmed for 2020-2021 but typically increases annually in line with inflation), (ii) contribution towards research costs, and (iii) tuition fees at the UK/EU rate.

Studentships will last for 3.5 years full-time.

References

Jonas KC, Chen S, Virta M, Mora J, Franks S, Huhtaniemi I, Hanyaloglu AC. (2018) Temporal reprogramming of calcium signalling via crosstalk of gonadotrophin receptors that associate as functionally asymmetric heteromers. Sci Rep. 8: 2239.

Kaushik Sarkar, Lisa Joedicke, Marta Westwood, Rebecca Burnley, Michael Wright, David McMillan, Bernadette Byrne (2019) Modulation of PTH1R signaling by an ECD binding antibody results in inhibition of β-arrestin 2 coupling. Sci. Rep. 9: 14432

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