Ligand-dependent conformational dynamics of the α2A-adrenergic receptor

Biased agonists targeting the α2A-adrenergic receptor (α2AAR) have therapeutic potential by preferentially engaging G protein signaling over β-arrestin pathways. Here, we used hydrogen-deuterium exchange mass spectrometry (HDX-MS) to compare α2AAR conformational dynamics across apo, agonist-bound, and GoA-coupled states. We analyzed HDX-MS changes induced by norepinephrine (NorEpi), the endogenous full agonist; dexmedetomidine (Dex), a clinically used full agonist that activates both Gi/o and β-arrestin signaling; and PS75, a Gi/o-biased partial agonist. By quantifying ligand-dependent differences in deuterium uptake and local dynamics, we aimed to define ligand-specific conformational ensembles. These findings provide mechanistic insight into partial agonism and suggest potential implications for biased signaling.