Molecular basis for high-affinity agonist binding in GPCRs

Science. 2019 May 24;364(6442):775-778. doi: 10.1126/science.aau5595. Epub 2019 May 9.


G protein-coupled receptors (GPCRs) in the G protein-coupled active state have higher affinity for agonists as compared with when they are in the inactive state, but the molecular basis for this is unclear. We have determined four active-state structures of the β1-adrenoceptor (β1AR) bound to conformation-specific nanobodies in the presence of agonists of varying efficacy. Comparison with inactive-state structures of β1AR bound to the identical ligands showed a 24 to 42% reduction in the volume of the orthosteric binding site. Potential hydrogen bonds were also shorter, and there was up to a 30% increase in the number of atomic contacts between the receptor and ligand. This explains the increase in agonist affinity of GPCRs in the active state for a wide range of structurally distinct agonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-1 Receptor Agonists / chemistry*
  • Adrenergic beta-1 Receptor Agonists / pharmacology
  • Allosteric Site / immunology
  • Catalytic Domain / immunology
  • Drug Design*
  • Hydrogen Bonding
  • Ligands
  • Protein Binding
  • Protein Structure, Secondary
  • Receptors, Adrenergic, beta-1 / chemistry
  • Receptors, Adrenergic, beta-1 / immunology
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / immunology
  • Single-Domain Antibodies / immunology


  • Adrenergic beta-1 Receptor Agonists
  • Ligands
  • Receptors, Adrenergic, beta-1
  • Receptors, G-Protein-Coupled
  • Single-Domain Antibodies