Structural Basis of the Diversity of Adrenergic Receptors

Cell Rep. 2019 Dec 3;29(10):2929-2935.e4. doi: 10.1016/j.celrep.2019.10.088.


Adrenergic receptors are highly homologous while at the same time display a wide diversity of ligand and G-protein binding, and understanding this diversity is key for designing selective or biased drugs for them. Here, we determine two crystal structures of the α2A adrenergic receptor (α2AAR) in complex with a partial agonist and an antagonist. Key non-conserved residues from the ligand-binding pocket (Phe7.39 and Tyr6.55) to G-protein coupling region (Ile34.51 and Lys34.56) are discovered to play a key role in the interplay between partial agonism and biased signaling of α2AAR, which provides insights into the diversity of ligand binding and G-protein coupling preference of adrenergic receptors and lays the foundation for the discovery of next-generation drugs targeting these receptors.

Keywords: GPCR; biased signaling; partial agonism; α(2A) adrenergic receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites / physiology
  • CHO Cells
  • Cell Line
  • Cricetulus
  • GTP-Binding Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Ligands
  • Protein Binding / physiology
  • Receptors, Adrenergic, alpha-2 / metabolism*
  • Signal Transduction / physiology


  • Ligands
  • Receptors, Adrenergic, alpha-2
  • GTP-Binding Proteins