Activation of the α2B adrenoceptor by the sedative sympatholytic dexmedetomidine

Nat Chem Biol. 2020 May;16(5):507-512. doi: 10.1038/s41589-020-0492-2. Epub 2020 Mar 9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-2 Receptor Agonists / chemistry*
  • Adrenergic alpha-2 Receptor Agonists / pharmacology
  • Animals
  • Binding Sites
  • Cryoelectron Microscopy
  • Dexmedetomidine / chemistry*
  • Dexmedetomidine / metabolism
  • Dexmedetomidine / pharmacology
  • GTP-Binding Proteins / chemistry
  • GTP-Binding Proteins / metabolism
  • Insecta / cytology
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Multiprotein Complexes / chemistry
  • Receptors, Adrenergic, alpha-2 / chemistry*
  • Receptors, Adrenergic, alpha-2 / genetics
  • Receptors, Adrenergic, alpha-2 / metabolism*
  • Sympatholytics / chemistry
  • Sympatholytics / pharmacology


  • ADRA2B protein, human
  • Adrenergic alpha-2 Receptor Agonists
  • Multiprotein Complexes
  • Receptors, Adrenergic, alpha-2
  • Sympatholytics
  • Dexmedetomidine
  • GTP-Binding Proteins