A role for a specific cholesterol interaction in stabilizing the Apo configuration of the human A(2A) adenosine receptor.
The function of G-protein-coupled receptors is tightly modulated by the lipid environment. Long-timescale molecular dynamics simulations (totaling approximately 3 mus) 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.
Lyman
Edward
E
Center for Biophysical Modeling and Simulation and Department of Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
Higgs
Chris
C
Schrödinger, L.L.C., 8910 University Center Lane, Suite 270, San Diego, CA 92122, USA.
Kim
Byungchan
B
Schrödinger, L.L.C., 120 West 45(th) Street, New York, NY 10036, USA.
Lupyan
Dmitry
D
Schrödinger, L.L.C., 120 West 45(th) Street, New York, NY 10036, USA; Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Shelley
John C
JC
Schrodinger, L.L.C., 101 S.W. Main Street, Suite 1300 Portland, OR 97204, USA.
Farid
Ramy
R
Schrödinger, L.L.C., 120 West 45(th) Street, New York, NY 10036, USA.
Voth
Gregory A
GA
Center for Biophysical Modeling and Simulation and Department of Chemistry, University of Utah, Salt Lake City, UT 84112, USA. Electronic address: voth@hec.utah.edu.
D001053:Apolipoproteins / Q000737:chemistry / Q000378:metabolism*; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D018047:Receptors, Purinergic P1 / Q000737:chemistry / Q000378:metabolism*
D001053:Apolipoproteins; D018047:Receptors, Purinergic P1; D002784:Cholesterol