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TitleDistinct binding conformations of epinephrine with α- and β-adrenergic receptors.
Journal, issue, pagesExp Mol Med, Vol. 56, Issue 9, Page 1952-1966, Year 2024
Publish dateSep 2, 2024
AuthorsJian-Shu Lou / Minfei Su / Jinan Wang / Hung Nguyen Do / Yinglong Miao / Xin-Yun Huang /
PubMed AbstractAgonists targeting α-adrenergic receptors (ARs) are used to treat diverse conditions, including hypertension, attention-deficit/hyperactivity disorder, pain, panic disorders, opioid and alcohol ...Agonists targeting α-adrenergic receptors (ARs) are used to treat diverse conditions, including hypertension, attention-deficit/hyperactivity disorder, pain, panic disorders, opioid and alcohol withdrawal symptoms, and cigarette cravings. These receptors transduce signals through heterotrimeric Gi proteins. Here, we elucidated cryo-EM structures that depict α-AR in complex with Gi proteins, along with the endogenous agonist epinephrine or the synthetic agonist dexmedetomidine. Molecular dynamics simulations and functional studies reinforce the results of the structural revelations. Our investigation revealed that epinephrine exhibits different conformations when engaging with α-ARs and β-ARs. Furthermore, α-AR and β-AR (primarily coupled to Gs, with secondary associations to Gi) were compared and found to exhibit different interactions with Gi proteins. Notably, the stability of the epinephrine-α-AR-Gi complex is greater than that of the dexmedetomidine-α-AR-Gi complex. These findings substantiate and improve our knowledge on the intricate signaling mechanisms orchestrated by ARs and concurrently shed light on the regulation of α-ARs and β-ARs by epinephrine.
External linksExp Mol Med / PubMed:39218975 / PubMed Central
MethodsEM (single particle)
Resolution2.8 - 3.2 Å
Structure data

EMDB-45425, PDB-9cbl:
Cryo-EM structure of epinephrine-bound alpha-2A-adrenergic receptor in complex with heterotrimeric Gi-protein
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-45426, PDB-9cbm:
Cryo-EM structure of dexmedetomidine-bound alpha-2A-adrenergic receptor in complex with heterotrimeric Gi-protein
Method: EM (single particle) / Resolution: 3.2 Å

Chemicals

ChemComp-ALE:
L-EPINEPHRINE / medication, hormone*YM

ChemComp-CZX:
4-[(1~{S})-1-(2,3-dimethylphenyl)ethyl]-1~{H}-imidazole / medication*YM

Source
  • homo sapiens (human)
  • rattus norvegicus (Norway rat)
  • bos taurus (domestic cattle)
  • enterobacteria phage t4 (virus)
KeywordsSIGNALING PROTEIN / GPCR / Adrenergic Receptor / GPCR Adrenergic Receptor

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