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SWBio DTP PhD project: Determining the conformational dynamics of the immune regulator STING and their control by STING ligands


Department of Pharmacy & Pharmacology

About the Project

Protein conformational dynamics – and the way in which these are influenced by small molecule ligands – are increasingly thought to underpin the mechanism of many biological processes. The protein STING (stimulator of interferon genes) regulates the interferon-mediated antiviral response and is activated by 2’,3’-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) in response to cytosolic DNA. STING is also activated by the presence of some pathogenic bacteria. Upon activation, bound cGAMP is sequestered from bulk solution within the STING dimer interface by closure of a 20-residue lid region, coupled to larger-scale conformational change. There is currently much commercial interest in the development of STING agonists for use in anti-cancer immunotherapy, however the underlying biophysical behaviour of STING (timescale and drivers of conformational change) remains poorly understood.

This project will address this gap by developing a fluorescence assay to report on STING conformational change in solution. We will characterise STING conformation in the presence and absence of small molecule ligands and determine the timescale of conformational change. We will probe conformational heterogeneity by performing experiments at the single molecule level and will carry out modelling to relate protein conformation and dynamics to ligand residence time. Our experimental equipment can capture events on timescales ranging from nanosecond to hours.

The project will be supervised by Dr Charlotte Dodson at University of Bath (lead academic supervisor), Dr Katie Chapman at MSD (Merck Sharp Dohme; industrial supervisor) and Prof Jean van den Elsen (University of Bath; second academic supervisor). It is suitable for students with a biological or physical science background who are interested in the physical behaviour of proteins and drug-target interactions. As part of the PhD, you will undertake a 6 month placement in the MSD laboratories at the Francis Crick Institute in London.

Key techniques: protein expression and labelling, single molecule fluorescence, mathematical modelling of equilibria, assay development, drug screening.

DTP SCHEME:

This project is one of a number that are in competition for funding from the South West Biosciences Doctoral Training Partnership (SWBio DTP) https://www.swbio.ac.uk/.

The DTP offers an interdisciplinary research training programme delivered by a consortium comprising the Universities of Bath, Bristol and Exeter, Cardiff University and Rothamsted Research, alongside six regional associate partners: Marine Biological Association, Plymouth Marine Laboratory, Swansea University, UCB Pharma, University of the West of England and SETsquared Bristol. The partnership has a strong track record in advancing knowledge through high quality research and teaching, in collaboration with industry and government.

Studentships are available for entry in October 2021.

All SWBio DTP projects will follow a structured 4-year PhD model, combining traditional project-focussed studies with a taught first year which includes directed rotation projects.

APPLICATIONS:

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.

Informal enquiries are welcomed and should be addressed to Dr Charlotte Dodson ().

Enquiries about the application process should be addressed to .

Formal applications should be submitted on the University of Bath’s online application form for a PhD in Biosciences: https://samis.bath.ac.uk/urd/sits.urd/run/siw_ipp_lgn.login?process=siw_ipp_app&code1=RDUBB-DT01&code2=0005

The closing date for applications is 7 December 2020.

Please ensure that you quote the supervisor’s name and project title in the ‘Your research interests’ section. You may apply for more than one project if you wish but you should submit a separate personal statement relevant to each one.

If you are an EU/EEA/Swiss national with settled or pre-settled status in the UK under the EU Settlement Scheme, please upload documentary evidence with your application.

More information about applying for a PhD at Bath may be found on our website https://www.bath.ac.uk/guides/how-to-apply-for-doctoral-study/.

Funding Notes

Studentships cover tuition fees at the ‘Home’ level, research/training costs and a stipend (£15,285 p.a., 2020/21 rate) for 3.5 years.

The main categories of candidates normally eligible for 'Home' fees are:
UK nationals*
Irish nationals living in the UK/Ireland
Applicants with settled or pre-settled* status in the UK under the EU Settlement Scheme
Applicants with indefinite leave to enter/remain in the UK

* must have lived in the UK/EEA/Switzerland continuously since September 2018.

Those not meeting the nationality and residency requirements to be treated as a ‘Home’ student may apply for a limited number of full studentships for international students.

References

Pan B-S, Perera SA, Piesvaux JA et al. (2020) Science 369:eaba6098 (STING and STING ligands)
Berger G, Marloye M, Lawler SE (2019) Trends Mol Med. 25:412-27 (STING in Cancer Immunotherapy)
Gilburt JAH, Sarkar H, … Dodson CA (2017) Angew Chem Int Ed Engl. 56:11409-14; Gilburt JAH, Girvan P, …Dodson CA (2019). Chem Sci. 10:4069-76 (experimental methodology)

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