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TitleActivation of the α adrenoceptor by the sedative sympatholytic dexmedetomidine.
Journal, issue, pagesNat Chem Biol, Vol. 16, Issue 5, Page 507-512, Year 2020
Publish dateMar 9, 2020
AuthorsDaopeng Yuan / Zhongmin Liu / Jonas Kaindl / Shoji Maeda / Jiawei Zhao / Xiaoou Sun / Jun Xu / Peter Gmeiner / Hong-Wei Wang / Brian K Kobilka /
PubMed AbstractThe α adrenergic receptors (αARs) are G protein-coupled receptors (GPCRs) that respond to adrenaline and noradrenaline and couple to the Gi/o family of G proteins. αARs play important roles in ...The α adrenergic receptors (αARs) are G protein-coupled receptors (GPCRs) that respond to adrenaline and noradrenaline and couple to the Gi/o family of G proteins. αARs play important roles in regulating the sympathetic nervous system. Dexmedetomidine is a highly selective αAR agonist used in post-operative patients as an anxiety-reducing, sedative medicine that decreases the requirement for opioids. As is typical for selective αAR agonists, dexmedetomidine consists of an imidazole ring and a substituted benzene moiety lacking polar groups, which is in contrast to βAR-selective agonists, which share an ethanolamine group and an aromatic system with polar, hydrogen-bonding substituents. To better understand the structural basis for the selectivity and efficacy of adrenergic agonists, we determined the structure of the αAR in complex with dexmedetomidine and Go at a resolution of 2.9 Å by single-particle cryo-EM. The structure reveals the mechanism of αAR-selective activation and provides insights into Gi/o coupling specificity.
External linksNat Chem Biol / PubMed:32152538
MethodsEM (single particle)
Resolution2.9 - 4.1 Å
Structure data

EMDB-9911, PDB-6k41:
cryo-EM structure of alpha2BAR-GoA complex
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-9912, PDB-6k42:
cryo-EM structure of alpha2BAR-Gi1 complex
Method: EM (single particle) / Resolution: 4.1 Å

Chemicals

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

Source
  • Spodoptera (butterflies/moths)
  • homo sapiens (human)
  • mus musculus (house mouse)
  • bos taurus (cattle)
  • enterobacteria phage rb59 (virus)
KeywordsMEMBRANE PROTEIN / GPCR / Complex / cryo-EM

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