Structural basis of agonist specificity of α 1A -adrenergic receptor

• Published in: Nature communications Vol. 14; no. 1; p. 4819
• Main Authors: Su, Minfei, Wang, Jinan, Xiang, Guoqing, Do, Hung Nguyen, Levitz, Joshua, Miao, Yinglong, Huang, Xin-Yun
• Format: Journal Article
• Language: English
• Published: England 10.08.2023
• Subjects: Epinephrine; Receptors, Adrenergic, alpha-1 - metabolism; Signal Transduction
• ISSN: 2041-1723

α -adrenergic receptors (α -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 α subtypes has limited our understanding of the physiological roles of different α -AR subtypes, and led to the stagnancy in agonist-based drug development for these receptors. Here we report cryo-EM structures of α -AR in complex with heterotrimeric G-proteins and either the endogenous common agonist epinephrine or the α -AR-specific synthetic agonist A61603. These structures provide molecular insights into the mechanisms underlying the discrimination between α -AR and α -AR by A61603. Guided by the structures and corresponding molecular dynamics simulations, we engineer α -AR mutants that are not responsive to A61603, and α -AR mutants that can be potently activated by A61603. Together, these findings advance our understanding of the agonist specificity for α -ARs at the molecular level, opening the possibility of rational design of subtype-specific agonists.