Structural basis of agonist specificity of α1A-adrenergic receptor

Minfei Su, Jinan Wang, Guoqing Xiang, Hung Nguyen Do, Joshua Levitz, Yinglong Miao () and Xin-Yun Huang ()
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Minfei Su: Weill Cornell Medical College of Cornell University
Jinan Wang: University of Kansas
Guoqing Xiang: Weill Cornell Medical College of Cornell University
Hung Nguyen Do: University of Kansas
Joshua Levitz: Weill Cornell Medical College of Cornell University
Yinglong Miao: University of Kansas
Xin-Yun Huang: Weill Cornell Medical College of Cornell University

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract α1-adrenergic receptors (α1-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 α1 subtypes has limited our understanding of the physiological roles of different α1-AR subtypes, and led to the stagnancy in agonist-based drug development for these receptors. Here we report cryo-EM structures of α1A-AR in complex with heterotrimeric G-proteins and either the endogenous common agonist epinephrine or the α1A-AR-specific synthetic agonist A61603. These structures provide molecular insights into the mechanisms underlying the discrimination between α1A-AR and α1B-AR by A61603. Guided by the structures and corresponding molecular dynamics simulations, we engineer α1A-AR mutants that are not responsive to A61603, and α1B-AR mutants that can be potently activated by A61603. Together, these findings advance our understanding of the agonist specificity for α1-ARs at the molecular level, opening the possibility of rational design of subtype-specific agonists.

Date: 2023
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DOI: 10.1038/s41467-023-40524-2

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