Uncovering the rules that govern inhibition of the Sec61 translocon, a druggable target in cancer, infection and immunity (ref FHMS - FF - 14 BIO)

We are seeking to recruit an enthusiastic and committed molecular/cell biologist to investigate the rules that govern the features of drugs and translocons that result in inhibition of translocation via Sec61.

Background:

The Sec61 translocon that imports proteins into the canonical secretory pathway is now emerging as a druggable target for cancer, chronic inflammation and viral infections (PMID:35434798, 29305616). Prof Simmonds’ lab recently discovered that a compound called mycolactone is a broad-span inhibitor of Sec61, and this drives the pathology of a bacterial disease called Buruli ulcer (PMID:24699819, 32692975). Mycobacterium ulcerans is an opportunistic environmental pathogen whose natural hosts and vectors are unknown. Genetically related bacteria make variants of mycolactone and preferentially infect fish or frogs, rather than mammals, but the reasons for this are not clear.

The project:

These (co-)evolutionary relationships now provide a unique model to understand the rules that govern translocation inhibition that will be broadly applicable in drug discovery. It will involve comparing the ability of different mycolactones to inhibit translocons from different parts of the evolutionary tree. To achieve this, you will receive training in a wide range of world-class molecular and cell biology research techniques, as well as molecular modelling (PMID:34726690). 

The impact:

Your discoveries will have impact on the development of better drugs that target Sec61 to kill cancer cells, prevent the production of inflammatory mediators and viral replication. Moreover, it will help solve the decades-old mystery of how Buruli ulcer is transmitted, by allowing us to understand why the bacteria retains the ability to make mycolactone despite the energetic cost.

The ideal candidate for this post would have a passionate interest in cell and molecular biology, be an aspiring ‘molecular detective’ and have a strong sense of curiosity. Applicants should have:

1. A first class undergraduate or master’s degree with distinction in molecular biology, cell biology, biochemistry or a closely allied discipline
2. Demonstrated aptitude for research
3. Motivation and enthusiasm for cell biology/microbiology
4. Evidence of capability to think and work independently

Your supervisors:

Your principal supervisor, Rachel Simmonds ([Email Address Removed]) is Professor of Immunopathogenesis and a world-leading expert in biological activity of mycolactone, the focus of this project. She is a molecular biologist by training, and (together with co-supervisor Dr Belinda Hall) discovered that mycolactone is an inhibitor of the Sec61 translocon. The co-supervisor, Dr Daniel Whelligan, is a medicinal chemist who helped develop methods for quantifying mycolactone binding to translocons. Training in molecular modelling comes from collaborator Prof Volkhard Helms at Saarland University (Germany; thee are opportunities to travel)

The Simmonds Lab values diversity and is committed to equality of opportunity.

Entry requirements

Open to UK and international students with the project starting in October 2023. Note that a maximum of 30% of the studentships will be offered to international students.

You will need to meet the minimum entry requirements for our PhD programme Biosciences and Medicine PhD research course | University of Surrey.

How to apply

Applicants are strongly encouraged to contact the relevant principal supervisor(s) to discuss the project(s) before submitting their application.

Applications should be submitted via the [https://www.surrey.ac.uk/postgraduate/biosciences-and-medicine-phd programme page (N.B. Please select the October 2023 start date when applying).

You may opt to apply for a single project or for 2 of these Faculty-funded studentship projects .

When completing your application, in place of a research proposal, please provide a brief motivational document (1 page maximum) which specifies:

• the reference numbers(s) for the project or two projects you are applying for
• the project title(s) and principal supervisor name(s)
• if applying for two projects, please also indicate your order of preference for the projects
• an explanation of your motivations for wanting to study for a PhD
• an explanation of your reasons for selecting the project(s) you have chosen

Additionally, to complete a full application, you MUST also email a copy of your CV and 1-page motivational document directly to the relevant project principal supervisor of each project you apply for. Due to short turnaround times for applicant shortlisting, failure to do this may mean that your application is not considered.

Please note that online interviews for shortlisted applicants are expected to take place during the week commencing 30^th January.