Molecular Mechanism for Ligand Recognition and Subtype Selectivity of α2C Adrenergic Receptor

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 α 2C adrenergic receptor (α 2C AR) with the non-selective antagonist, RS79948, at 2.8 Å. Our structure, mutations, modeling, and functional experiments indicate that a α 2C AR-specific D206 ECL2 -R409 ECL3 -Y405 6.58 network plays a role in determining α 2 adrenergic subtype selectivity. Furthermore, our results show that a specific loosened helix at the top of TM4 in α 2C AR is involved in receptor activation. Together, our structure of human α 2C AR-RS79948 provides key insight into the mechanism underlying the α 2 adrenergic receptor activation and subtype selectivity.