Intracellular Receptor Modulation: Novel Approach to Target GPCRs

Trends Pharmacol Sci. 2018 Jun;39(6):547-559. doi: 10.1016/j.tips.2018.03.002. Epub 2018 Apr 10.

Abstract

Recent crystal structures of multiple G protein-coupled receptors (GPCRs) have revealed a highly conserved intracellular pocket that can be used to modulate these receptors from the inside. This novel intracellular site partially overlaps with the G protein and β-arrestin binding site, providing a new manner of pharmacological intervention. Here we provide an update of the architecture and function of the intracellular region of GPCRs, until now portrayed as the signaling domain. We review the available evidence on the presence of intracellular binding sites among chemokine receptors and other class A GPCRs, as well as different strategies to target it, including small molecules, pepducins, and nanobodies. Finally, the potential advantages of intracellular (allosteric) ligands over orthosteric ligands are also discussed.

Keywords: G protein-coupled receptors; allosteric modulation; antagonism; intracellular binding site; small molecules.

Publication types

  • Review

MeSH terms

  • Allosteric Regulation / drug effects*
  • Allosteric Site
  • Drug Delivery Systems
  • Drug Design*
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Targeted Therapy
  • Protein Conformation
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction
  • Small Molecule Libraries* / chemistry
  • Small Molecule Libraries* / metabolism

Substances

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