MRC DiMeN Doctoral Training Partnership: Biochemical and Cryo-EM analysis of cancer-causing pseudokinases

Supervisory team:
Professor Patrick Eyers (Biochemistry, Liverpool, Lead supervisor)
https://www.liverpool.ac.uk/integrative-biology/staff/patrick-eyers/

Dr Elton Zeqiraj (Astbury Centre, Leeds, 2nd supervisor)
http://www.astbury.leeds.ac.uk/people/staff/staffpage.php?StaffID=EZ

Key dates:
Deadline for application: 21st January 2019
Start date: 1st October 2019

Project description:
Protein kinases drive all aspects of cell signalling and are outstanding drug targets in human diseases such as cancer. Pseudokinases are catalytically-deficient variants of kinases with a similar fold and druggability, and represent an important new group of drug targets. The focus of this project is the Tribbles family of pseudokinases, which control the signaling activity and stability of ‘canonical’ protein kinases such as AKT and MEK. By manipulating Tribbles levels in cells, we aim to sensitise and kill drug-resistant cancer cells.

We recently found that Tribbles pseudokinases control cell signalling via the formation of druggable signalling complexes. However, we know almost nothing about pseudokinase structural dynamics within protein complexes, or how this is perturbed by disease-modifying drugs. We will train a PhD student in state-of-the-art biochemical and cryo-EM structural approaches to establish how Tribbles signaling complexes are regulated and can be drugged.

Based at the University of Liverpool, this 3.5 year studentship takes advantage of the fact that macromolecular (pseudo)kinase signalling complexes can be structually defined by cryo-EM in the presence of drugs. Our analysis will inform other work in this area, and help reveal how pseudokinases control signalling in cancer cells.

This project is a collaboration between two well-funded research groups at the University of Liverpool and the University of Leeds, and focuses on approved or late-phase clinical drugs that we believe have potential for eliminating Tribbles-associated cancer cells. It also represents a superb multidisciplinary training opportunity that addresses MRC strategic research and skill priorities. It is a two-way collaboration between Professor Patrick Eyers (Department of Biochemistry, University of Liverpool) and Dr Elton Zeqiraj (Astbury Centre, University of Leeds), both of whom have international portfolios in student training. The project would suit ambitious Life Sciences graduates with an interest in cell signaling, cancer research, protein kinases and drug discovery, likely to include a degree in molecular biosciences, such as biochemistry, molecular biology, biophysics or biological sciences.

The major scientific scientific goals of the PhD project are:

• Biochemical and cryo-EM analysis of Tribbles pseudokinases and substrate complexes in the presence and absence of clinically-approved drugs
• Development of cellular pipelines to evaluate how covalent compounds regulate Tribbles signalling complexes
• Translation of findings into disease models to evaluate Tribbles signalling in human cancer

In terms of training, key outcomes for the student include:

• Immersion in state-of-the art pseudokinase and cryo-EM signalling research in internationally-leading laboratories
• Member of an MRC training network merging (pseudo)kinase chemical Biology and Drug Discovery (Liverpool) and the Astbury Centre for Structural Molecular Biology (Leeds)
• A portfolio of training in critical, and highly employable, skill sets including protein purification, cry-electron microscopy, drug-binding and the quantitative analysis of cell signaling

Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website:
http://www.dimen.org.uk/