Abstract
Adrenergic G-protein-coupled receptors (GPCRs) mediate different cellular signaling pathways in the presence of endogenous catecholamines and play important roles in both physiological and pathological conditions. Extensive studies have been carried out to investigate the structure and function of β adrenergic receptors (βARs). However, the structure of α adrenergic receptors (αARs) remains to be determined. Here, we report the structure of the human α2C adrenergic receptor (α2CAR) with the non-selective antagonist, RS79948, at 2.8 Å. Our structure, mutations, modeling, and functional experiments indicate that a α2CAR-specific D206ECL2-R409ECL3-Y4056.58 network plays a role in determining α2 adrenergic subtype selectivity. Furthermore, our results show that a specific loosened helix at the top of TM4 in α2CAR is involved in receptor activation. Together, our structure of human α2CAR-RS79948 provides key insight into the mechanism underlying the α2 adrenergic receptor activation and subtype selectivity.