Decoding the Molecular Mechanisms of GPCR Biased Signalling

G protein coupled receptors (GPCRs) are central regulators of human physiology and the most successful class of drug targets. However, many GPCR-targeting drugs activate multiple signalling pathways, leading to undesirable side effects. Biased signalling, where ligands preferentially activate specific GPCR pathways, offers a promising route to more selective therapies. Yet, the molecular mechanisms underlying this bias remain unknown, limiting the development of next-generation drugs. This project will clarify how biased signalling is shaped by the interplay between ligand binding, receptor conformation, phosphorylation, and effector recruitment. Building on my work developing advanced backbone NMR methods for GPCRs, I will investigate how ligand-induced conformational changes in the receptor core propagate to disordered intracellular regions targeted by GPCR kinases. These phosphorylated segments form key regulatory sites that are often inaccessible to other structural techniques. By combining structural insights with biochemical and cellular assays, I will examine the β1-adrenergic receptor as a clinically relevant and well characterised model. This framework will be extended to GPR3, an understudied receptor whose dysregulation is implicated in metabolic and neurodegenerative disorders. This research will shift the field from static views of receptor activation to a dynamic model of signalling specificity, guiding the design of functionally selective ligands.