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