Structural basis of agonist specificity of α1A-adrenergic receptor

& alpha;(1)-adrenergic receptors (& alpha;(1)-ARs) play critical roles in the cardiovascular and nervous systems where they regulate blood pressure, cognition, and metabolism. However, the lack of specific agonists for all & alpha;(1) subtypes has limited our understanding of the physiological roles of different & alpha;(1)-AR subtypes, and led to the stagnancy in agonist-based drug development for these receptors. Here we report cryo-EM structures of & alpha;(1A)-AR in complex with heterotrimeric G-proteins and either the endogenous common agonist epinephrine or the & alpha;(1A)-AR-specific synthetic agonist A61603. These structures provide molecular insights into the mechanisms underlying the discrimination between & alpha;(1A)-AR and & alpha;(1B)-AR by A61603. Guided by the structures and corresponding molecular dynamics simulations, we engineer & alpha;(1A)-AR mutants that are not responsive to A61603, and & alpha;(1B)-AR mutants that can be potently activated by A61603. Together, these findings advance our understanding of the agonist specificity for & alpha;(1)-ARs at the molecular level, opening the possibility of rational design of subtype-specific agonists. & alpha;1-adrenergic receptors (& alpha;1- AR) play critical roles in the cardiovascular and nervous systems. Here, the authors report molecular insights into the mechanisms underlying the discrimination between & alpha;1A-AR and & alpha;1B-AR by the agonist A61603.