Structural basis of agonist specificity of α<sub>1A</sub>-adrenergic receptor.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 37563160.
- Also identified by DOI 10.1038/s41467-023-40524-2 and PMC identifier 10415349.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
α<sub>1</sub>-adrenergic receptors (α<sub>1</sub>-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<sub>1</sub> subtypes has limited our understanding of the physiological roles of different α<sub>1</sub>-AR subtypes, and led to the stagnancy in agonist-based drug development for these receptors. Here we report cryo-EM structures of α<sub>1A</sub>-AR in complex with heterotrimeric G-proteins and either the endogenous common agonist epinephrine or the α<sub>1A</sub>-AR-specific synthetic agonist A61603. These structures provide molecular insights into the mechanisms underlying the discrimination between α<sub>1A</sub>-AR and α<sub>1B</sub>-AR by A61603. Guided by the structures and corresponding molecular dynamics simulations, we engineer α<sub>1A</sub>-AR mutants that are not responsive to A61603, and α<sub>1B</sub>-AR mutants that can be potently activated by A61603. Together, these findings advance our understanding of the agonist specificity for α<sub>1</sub>-ARs at the molecular level, opening the possibility of rational design of subtype-specific agonists.
Medical subject headings
- Receptors, Adrenergic, alpha-1
- Epinephrine