Ligand binding and micro-switches in 7TM receptor structures

Trends Pharmacol Sci. 2009 May;30(5):249-59. doi: 10.1016/ Epub 2009 Apr 16.


The past couple of years have seen several novel X-ray structures of 7 transmembrane (7TM) receptors in complex with antagonists and even with a peptide fragment of a G protein. These structures demonstrate that the main ligand-binding pocket in 7TM receptors is like a funnel with a partial 'lid' in which extracellular loop 2b, in particular, functions as a gating element. Small-molecule antagonists and inverse agonists bind in very different modes: some very deeply and others more superficially, even reaching out above the transmembranes. Several highly conserved residues seem to function as micro-switches of which ArgIII:26 (Arg3.50) in its active conformation interacts directly with the G protein. These micro-switches together with a hydrogen-bond network between conserved polar residues and structural water molecules are proposed to constitute an extended allosteric interface between the domains (i.e. especially TM-VI), which performs the large, global toggle switch movements connecting ligand binding with intracellular signaling.

Publication types

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

MeSH terms

  • Allosteric Regulation
  • Binding Sites
  • Drug Agonism
  • Drug Antagonism
  • Ligands
  • Models, Molecular*
  • Molecular Conformation
  • Molecular Structure
  • Protein Interaction Domains and Motifs*
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, G-Protein-Coupled / chemistry*


  • Ligands
  • Receptors, G-Protein-Coupled
  • seven-transmembrane G-protein-coupled receptor