Mechanisms for differential GPCR:effector coupling

Principal Advisor: Dr Sebastian Furness

Organisational unit: School of Biomedical Sciences

Research group: Furness Group - Laboratory of receptor transducer coupling

G protein coupled receptors can be activated to a varied extent by different ligands. This is the basis for partial efficacy, which has been exploited for a subset of medicines. We have previously shown that the calcitonin receptor, when activated by different peptides, stimulates distinct rates of nucleotide exchange at its G protein transducer. This occurs due to a ligand-promoted difference in the nucleotide affinity of the G protein. Unanswered is the question of whether this is due to absolute conformational differences or differences in protein dynamics. The project will involve the use of bi-orthogonal fluorescent labeling strategies on G proteins. Interaction of these fluorescent labels will then be investigated using single molecule dynamics with an emphasis on the utility of (Fluorescence Lifetime Imaging Microscopy – Fluorescence Resonance Energy Transfer) FLIM-FRET in addition to a suite of other techniques.