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

Summary The function of G-protein-coupled receptors is tightly modulated by the lipid environment. Long-timescale molecular dynamics simulations (totaling ∼3 μs) of the A 2A 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 A 2A receptor couples to G protein only in the presence of cholesterol (Zezula and Freissmuth, 2008). The results suggest a mechanism by which the A 2A 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.