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Title | Structural basis of agonist specificity of α-adrenergic receptor. |
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Journal, issue, pages | Nat Commun, Vol. 14, Issue 1, Page 4819, Year 2023 |
Publish date | Aug 10, 2023 |
Authors | Minfei Su / Jinan Wang / Guoqing Xiang / Hung Nguyen Do / Joshua Levitz / Yinglong Miao / Xin-Yun Huang / |
PubMed Abstract | 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 ...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. |
External links | Nat Commun / PubMed:37563160 / PubMed Central |
Methods | EM (single particle) |
Resolution | 2.6 - 3.1 Å |
Structure data | EMDB-41267, PDB-8thk: EMDB-41268, PDB-8thl: |
Chemicals | ChemComp-CGZ: ChemComp-ALE: |
Source |
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Keywords | SIGNALING PROTEIN / Alpha-1A-adrenergic receptor / A61603 / Epinephrine |