Activation mechanism of the μ-opioid receptor by an allosteric modulator

Abstract

Significance The allosteric modulators, which bind to nonorthosteric sites to enhance the signaling activities of G-protein-coupled receptors (GPCRs), are new candidates for GPCR-targeting drugs. Our solution NMR analyses of the μ-opioid receptor (MOR) revealed that the MOR activity was determined by a conformational equilibrium between three conformations. Interestingly, an allosteric modulator shifted the equilibrium toward a conformation with the highest activity to a level that cannot be reached by orthosteric ligands alone, leading to the increased activity of MOR. Our NMR analyses also identified the binding site of the allosteric modulator, including the residues contributing to the regulation of the equilibrium. These findings provide insights into the rational developments of novel allosteric modulators.