Abstract
Based on molecular modeling of the complexes between the µ-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.
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