Molecular Mechanism for Ligand Recognition and Subtype Selectivity of α 2C 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.
(Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)