Novel Allosteric Modulators of G Protein-coupled Receptors

J Biol Chem. 2015 Aug 7;290(32):19478-88. doi: 10.1074/jbc.R115.662759. Epub 2015 Jun 22.


G protein-coupled receptors (GPCRs) are allosteric proteins, because their signal transduction relies on interactions between topographically distinct, yet conformationally linked, domains. Much of the focus on GPCR allostery in the new millennium, however, has been on modes of targeting GPCR allosteric sites with chemical probes due to the potential for novel therapeutics. It is now apparent that some GPCRs possess more than one targetable allosteric site, in addition to a growing list of putative endogenous modulators. Advances in structural biology are also shedding new insights into mechanisms of allostery, although the complexities of candidate allosteric drugs necessitate rigorous biological characterization.

Keywords: G protein; G protein-coupled receptor (GPCR); allosteric regulation; biased agonism; bitopic ligand; chemical biology; drug discovery; structural biology.

Publication types

  • Historical Article
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Allosteric Regulation
  • Allosteric Site / drug effects
  • Crystallography, X-Ray / history
  • Drug Design*
  • History, 21st Century
  • Humans
  • Ligands
  • Models, Molecular
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship


  • Ligands
  • Receptors, G-Protein-Coupled
  • Small Molecule Libraries