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Structural basis of agonist specificity of α1A-adrenergic receptor
Su, Minfei Wang, Jinan Xiang, Guoqing Do, Hung Nguyen Levitz, Joshua Miao, Yinglong Huang, Xin-Yun
Su, Minfei
Wang, Jinan
Xiang, Guoqing
Do, Hung Nguyen
Levitz, Joshua
Miao, Yinglong
Huang, Xin-Yun
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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.
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Date
2023-08-10
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Nature Research
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Keywords
Cryoelectron microscopy, Receptor pharmacology, Adrenal cortex hormones, Cardiac hypertrophy, Permeation and transport
Citation
Su M, Wang J, Xiang G, Do HN, Levitz J, Miao Y, Huang XY. Structural basis of agonist specificity of α1A-adrenergic receptor. Nat Commun. 2023 Aug 10;14(1):4819. doi: 10.1038/s41467-023-40524-2. PMID: 37563160; PMCID: PMC10415349