A Role for a Specific Cholesterol Interaction in Stabilizing the Apo Configuration of the Human A2A Adenosine Receptor

摘要

The function of G-protein-coupled receptors is tightly modulated by the lipid environment. Long-timescale molecular dynamics simulations (totaling 3 ms) of the A2A receptor in cholesterol-free bilayers, with and without the antagonist ZM241385 bound, demonstrate the instability of helix II in the apo receptor in cholesterol-poor membrane regions. We directly observe that the effect of cholesterol binding is to stabilize helix II against a buckling-type deformation, perhaps rationalizing the observation that the A2A receptor couples toGprotein only in the presence of cholesterol (Zezula and Freissmuth, 2008). The results suggest a mechanism by which the A2A receptor may function as a coincidence detector, activating only in the presence of both cholesterol and agonist. We also observed a previously hypothesized conformation of the tryptophan ‘‘rotameric switch’’ on helix VI in which a phenylalanine on helix V positions the tryptophan out of the ligand binding pocket.