Ligand-specific restriction of extracellular conformational dynamics constrains signaling of the M(2) muscarinic receptor


  • M. Bermudez
  • A. Bock
  • F. Krebs
  • U. Holzgrabe
  • K. Mohr
  • M.J. Lohse
  • G. Wolber


  • ACS Chemical Biology


  • ACS Chem Biol 12 (7): 1743-1748


  • G protein-coupled receptors transmit extracellular signals across cell membranes via different G protein classes and {beta}-arrestins. Some pathways may be therapeutically beneficial, whereas others may be detrimental under certain pathophysiological conditions. For many GPCRs, biased agonists are available, which preferentially signal through one pathway or a subset of pathways, and harnessing biased agonism could be a potential novel therapeutic strategy. However, the incomplete mechanistic understanding of biased agonism hampers rational design of biased ligands. Using the muscarinic M(2) receptor as a model system, we have analyzed the relationship between ligand-dependent conformational changes as revealed in all-atom MD simulations and the activation of specific G proteins. We find that the extent of closure of the extracellular, allosteric binding site interferes with the activation of certain G proteins. Our data allow the rational design of Gi-biased agonists at the M(2) receptor and delineate a simple principle which may be translated to other GPRCs.