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TitleStructural basis of α-adrenergic receptor activation and recognition by an extracellular nanobody.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 3655, Year 2023
Publish dateJun 20, 2023
AuthorsYosuke Toyoda / Angqi Zhu / Fang Kong / Sisi Shan / Jiawei Zhao / Nan Wang / Xiaoou Sun / Linqi Zhang / Chuangye Yan / Brian K Kobilka / Xiangyu Liu /
PubMed AbstractThe αadrenergic receptor (αAR) belongs to the family of G protein-coupled receptors that respond to adrenaline and noradrenaline. αAR is involved in smooth muscle contraction and cognitive ...The αadrenergic receptor (αAR) belongs to the family of G protein-coupled receptors that respond to adrenaline and noradrenaline. αAR is involved in smooth muscle contraction and cognitive function. Here, we present three cryo-electron microscopy structures of human αAR bound to the endogenous agonist noradrenaline, its selective agonist oxymetazoline, and the antagonist tamsulosin, with resolutions range from 2.9 Å to 3.5 Å. Our active and inactive αAR structures reveal the activation mechanism and distinct ligand binding modes for noradrenaline compared with other adrenergic receptor subtypes. In addition, we identified a nanobody that preferentially binds to the extracellular vestibule of αAR when bound to the selective agonist oxymetazoline. These results should facilitate the design of more selective therapeutic drugs targeting both orthosteric and allosteric sites in this receptor family.
External linksNat Commun / PubMed:37339967 / PubMed Central
MethodsEM (single particle)
Resolution2.92 - 3.52 Å
Structure data

33924

7ym8

EMDB-33924, PDB-7ym8:
Cryo-EM structure of Nb29-alpha1AAR-miniGsq complex bound to oxymetazoline
Method: EM (single particle) / Resolution: 2.92 Å

33928

7ymh

EMDB-33928, PDB-7ymh:
Cryo-EM structure of Nb29-alpha1AAR-miniGsq complex bound to noradrenaline
Method: EM (single particle) / Resolution: 3.52 Å

33930

7ymj

EMDB-33930, PDB-7ymj:
Cryo-EM structure of alpha1AAR-Nb6 complex bound to tamsulosin
Method: EM (single particle) / Resolution: 3.35 Å

Chemicals

ChemComp-J5C:
Oxymetazoline / medication*YM / Oxymetazoline

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-E5E:
Noradrenaline / neurotransmitter, hormone*YM / Norepinephrine

ChemComp-JGX:
Tamsulosin

Source
  • synthetic construct (others)
  • homo sapiens (human)
  • lama glama (llama)
KeywordsMEMBRANE PROTEIN / GPCR / Nanobody / Agonist / Complex / Antagonist

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