Structural biology
Advances in cryo-electron microscopy (cryo-EM) are revolutionising membrane biology and molecular pharmacology. It is now possible to visualize challenging biological macromolecules, such as membrane proteins, at near-atomic resolution in different conformational states, bound to different ligands, and in complex with small-molecule drugs as well as protein binders in a native-like lipid environment. A key advantage of the single-particle cryo-EM workflow is its ability to address conformational heterogeneity within the imaged sample, with the potential of uncovering unique structural landscapes. In our lab, we are interested in using this technique to understand the molecular mechanism of membrane transport, signalling, and excitability by taking structural snapshots of key membrane proteins in functionally relevant states and in a cellular context.
Function and dynamics
Like most other proteins, channels and scramblases are dynamic molecules that perform their biological function by undergoing regulated conformational changes. Some of these functionally important states, however, can at times be difficult to capture using structural biology techniques. One of our main interests is to combine electrophysiology, quantitative analysis, and complementary biophysical approaches such as single-molecule spectroscopy to study these seemingly hidden transitions. This will allow us to understand how the function and dynamics of these proteins are modulated by perturbations such as mutations and other physiological and novel pharmacological ligands.
Development of precision therapeutics
Many prescribed drugs, including commonly used anti-hypertensive drugs and anti-depressants, target receptors, channels, and transporters, but despite these successful examples, many potentially disease-modifying membrane proteins remain undruggable. Our lab is interested in discovering and optimizing small and large molecules that would exert the desired pharmacological effects on our targets of interest. We aim to combine the above approaches with de novo protein design and medicinal chemistry to create and validate new chemical compounds and biologics for key membrane proteins. Together with rigorous experimental characterisation, we seek to understand how specific and potent modulators can act and be developed and translate these advances into real-life applications.