Probing the correlation between ligand efficacy and conformational diversity at the α 1A-adrenoreceptor reveals allosteric coupling of its microswitches

J Biol Chem. 2020 May 22;295(21):7404-7417. doi: 10.1074/jbc.RA120.012842. Epub 2020 Apr 17.


G protein-coupled receptors (GPCRs) use a series of conserved microswitches to transmit signals across the cell membrane via an allosteric network encompassing the ligand-binding site and the G protein-binding site. Crystal structures of GPCRs provide snapshots of their inactive and active states, but poorly describe the conformational dynamics of the allosteric network that underlies GPCR activation. Here, we analyzed the correlation between ligand binding and receptor conformation of the α1A-adrenoreceptor, a GPCR that stimulates smooth muscle contraction in response to binding noradrenaline. NMR of [13CϵH3]methionine-labeled α1A-adrenoreceptor variants, each exhibiting differing signaling capacities, revealed how different classes of ligands modulate the conformational equilibria of this receptor. [13CϵH3]Methionine residues near the microswitches exhibited distinct states that correlated with ligand efficacies, supporting a conformational selection mechanism. We propose that allosteric coupling among the microswitches controls the conformation of the α1A-adrenoreceptor and underlies the mechanism of ligand modulation of GPCR signaling in cells.

Keywords: G protein-coupled receptor (GPCR); adrenergic receptor; allosteric coupling; binding mechanism; conformational change; conformational equilibrium; ligand-binding protein; microswitch; nuclear magnetic resonance (NMR); solution structure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Crystallography, X-Ray
  • Humans
  • Ligands
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Conformation
  • Receptors, Adrenergic, alpha-1 / chemistry*
  • Receptors, Adrenergic, alpha-1 / metabolism


  • ADRA1A protein, human
  • Ligands
  • Receptors, Adrenergic, alpha-1