I am a biophysicist with an interdisciplinary research group working at the interface of the biological and physical sciences. We use single molecule fluorescence spectroscopy and other techniques to measure changes in the conformation of protein drug targets with the ultimate aim of using our results to improve drug discovery. Our approach enables us to detect and quantify multiple populations in solution and to observe transient occupation of minority states directly. In particular, we specialise in measuring small distance changes and conformational changes in small proteins using dye quenching.

Protein kinases

Protein kinases regulate many cellular processes and are a major class of drug target, particularly in inflammation and oncology. Broadly speaking, x-ray structures show kinases in one of two major conformations which regulate kinase catalytic activity and are thought to influence the binding of kinase inhibitors. However, until recently, very little was known about whether individual molecules were locked in a single conformation or were in conformational equilibrium, whether this was driven by inhibitor binding, or what the timescale of any interconversion was.

By covalently attaching bright fluorescent dyes to known sites on the kinase surface, we directly measured the dynamic interconversion of a protein kinase between DFG-in-like active and DFG-out-like inactive conformations in solution for the first time. Among other discoveries, we have shown that the position of equilibrium can be changed by kinase ligands (eg physiological activators and drug-like inhibitors) and that ligand-bound kinase can also interconvert between conformations. This is a new way of thinking about kinase inhibition and there are many implications of our results, including how best to incorporate multiple protein structures into the process of structure-based drug design.

About Charlotte

I carried out my PhD research in protein folding at the MRC Centre for Protein Engineering (Cambridge, UK) in the lab of Alan Fersht. I then moved to work with Richard Bayliss on protein kinases at the Institute of Cancer Research, before a second postdoc in spectroscopy, microscopy and magnetoreception with Mark Wallace and Peter Hore at University of Oxford (where I also held a Fulford Junior Research Fellowship at Somerville College). In 2013 I won an Imperial College Research Fellowship to apply single molecule techniques to protein kinases and start my own research group at Imperial College London. I have worked in biophysics, structural biology, chemistry and biomedical departments before moving to Pharmacy & Pharmacology at University of Bath in 2018.

I welcome motivated PhD students with a biological or physical science background who are interested in the physical measurement of biological molecules, drug discovery, mechanism of inhibition, image analysis or optics. I will have one funded place to start in October 2020 for a UK or EU student, but am also very interested to hear from international students who have identified competitive sources of funding for which we might apply together.

If you intend to apply for a scholarship please contact me well advance of your intended start date as there are University deadlines in addition to those of your funder.