Activation of the α2B adrenoceptor by the sedative sympatholytic dexmedetomidine.

Nature Chemical Biology
Daopeng YuanBrian K Kobilka

Abstract

The α2 adrenergic receptors (α2ARs) are G protein-coupled receptors (GPCRs) that respond to adrenaline and noradrenaline and couple to the Gi/o family of G proteins. α2ARs play important roles in regulating the sympathetic nervous system. Dexmedetomidine is a highly selective α2AR 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 α2BAR in complex with dexmedetomidine and Go at a resolution of 2.9 Å by single-particle cryo-EM. The structure reveals the mechanism of α2AR-selective activation and provides insights into Gi/o coupling specificity.

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Citations

Nov 4, 2020·European Journal of Medicinal Chemistry·Michela McMullanIsabel Rozas
Jul 3, 2021·Biomolecules·Yiran WuSuwen Zhao
Aug 7, 2021·Nature Structural & Molecular Biology·Hiroyuki H OkamotoOsamu Nureki

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