Towards Structural and Pharmacological Characterisation of Orphan GPCRs

This thesis leverages constitutive activity to overcome ligand dependence and enable structural and functional analyses of class A orphan G protein-coupled receptors (GPCRs). For GPR151, a sensitive assay revealed context-dependent, pH-enhanced coupling to specific G proteins and potential initial complexes for future structural work. For GPR3, single-particle cryo-EM structures with the lipids show a dynamic region permitting promiscuous long-chain lipid binding and distinct conformational dynamics. Together, these results clarify activation mechanisms in orphan GPCRs.