Inhibition Molecular Mechanism of α ₂ Adrenergic Receptor Activation by Antagonist

The α_2A adrenergic receptor (α_2AAR) and α_2B adrenergic receptor (α_2BAR) are G protein-coupled receptors (GPCRs) that mediate important physiological functions in response to the endogenous neurotransmitters norepinephrine and epinephrine. Antagonist drugs targeting α₂ARs have been widely used for many years. However, current structural studies of drug-receptor complexes are insufficient to elucidate their interactions. Here, to uncover the molecular mechanisms of antagonist drug actions, we determine the cryo-electron microscopy (cryo-EM) structures of α_2AAR bound to phentolamine and α_2BAR bound to phenoxybenzamine. Together with the mutagenesis data, these results provide insights into the molecular basis of ligand recognition and antagonism at α_2AAR and α_2BAR. Overall, our studies contribute to a deeper understanding of adrenergic receptor modulation and provide some clues for the development of novel antagonists.