abstract
- Based on molecular modeling of the complexes between the mu-opioid receptor and its ligands, we present a hypothesis that accounts for several of the experimental data including the importance of conserved polar residues in rhodopsin-like G-protein-coupled receptors and the effect of Na+ on the binding of ligands to these receptors. We propose that agonists, but not antagonists, would displace Na+ from its initial binding site at the conserved D2.50 residue in the second transmembrane alpha-helical segment, H2. The displaced Na+ would pass through a "gate" of conserved hydrophobic residues and move along a tunnel-like interface (formed of H2, H3 and H7) enriched with several conserved hydrophilic residues including D3.49. Interaction of Na+ with D3.49 would result in the breaking of a salt-bridge between D3.49 and the conserved R3.50 residue thus exposing the latter for interaction with the G-protein.