Investigating the structure and dynamics of G protein-coupled receptors by EPR Spectroscopy and other cutting-edge methodogies

Membrane proteins (MPs) make up a significant part of the genome and are the target of ~30% of therapeutics and yet our structural and functional understanding often lags behind their soluble counterparts. G protein-coupled receptors (GPCRs) are the largest family of membrane proteins and mediate most of physiological responses to hormones and environmental
stimulants and are responsible for olfaction, vision and taste. GPCRs account for 50% of all MP targets and are expressed ubiquitously in humans. Exciting new developments in Structural EPR spectroscopy, which allows for accurate distance measurements between spin pairs introduced on selected protein sites, have changed the way we can study membrane protein structure and provide new insights into our fundamental understanding in their dynamics to drive therapeutic design.
This project will combine advanced structural EPR spectroscopy, complemented by Mass spectrometry and CryoEM to probe GPCR dynamics, using a variety of cutting edge techniques and make use of the new BioEmPiRe centre, in addition to collaborating with the National Research Facility for EPR in Manchester. Work will focus on Cannabinoid 1 (CB1) receptor, which is mainly expressed in the brain and is responsible for many of the psychoactive effects of cannabinoids and Cannabinoid 2 (CB2) receptor, which has a more localised distribution, being expressed in several immune cells and neurones.
By understanding the role of receptor dynamics on GPCR activation and ligand activity, we are aiming to provide new insights into small molecule drug action mechanism that could be used to develop novel more efficacious drugs. The successful PhD student will be trained in complementary cutting edge techniques of interest to both academia and the collaborating company Z7 Biotech Ltd, our industrial partner in this project.