Allosterism and ligand-bias at the immunometabolic receptor GPR84
Supervisors:
Graeme Milligan, School of Molecular Biosciences, University of Glasgow
Irina G Tikhonova, School of Pharmacy, Queen’s University Belfast
Summary:
G protein-coupled receptors (GPCRs) remain the major target class for designing new medicines, with structure-based drug design and computational analysis now routinely supporting therapeutic target validation and novel regulatory strategies. Our recently obtained cryo-EM structures of GPR84 with ligands exhibiting varying pharmacological profiles provide a unique opportunity to develop more effective strategies for immune cell function, particularly in cancer cell phagocytosis.
This project exploits GPR84's complex pharmacology, where biased orthosteric agonists selectively activate G protein signalling while avoiding arrestin recruitment, and allosteric modulators can dramatically alter this bias profile. Students will characterize functional interactions between orthosteric and allosteric ligands using structure-guided mutagenesis and molecular dynamics simulations, perform virtual screening to identify novel allosteric modulators, validate findings in primary neutrophils and macrophages from knockout mice, and assess therapeutic potential for enhancing cancer cell phagocytosis.
The interdisciplinary training spans computational drug discovery, structural pharmacology, and cellular immunology, creating highly versatile graduates. Students will master molecular dynamics simulations, structure-based virtual screening, site-directed mutagenesis, advanced pharmacological assays, and primary immune cell culture techniques. This integration of computational and experimental approaches, combined with translational validation in disease-relevant models, provides exceptional preparation for careers in academic research or pharmaceutical industry, particularly in immunomodulatory therapeutics development.