Biochemical and Cryo-EM analysis of cancer-causing pseudokinases

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.

This project takes advantage of the fact that macromolecular (pseudo)kinase signalling complexes can be structurally 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.

The major scientific goals of the PhD project are:
1. Biochemical and cryo-EM analysis of Tribbles pseudokinases and substrate complexes in the presence and absence of clinically-approved drugs
2. Development of cellular pipelines to evaluate how covalent compounds regulate Tribbles signalling complexes
3. Translation of findings into disease models to evaluate Tribbles signalling in human cancer