GPCR A2AAR Agonist Binding and Induced Conformation Changes of Functional Switches

Abstract

Agonist binding of A2A adenosine receptor (A2AAR) shows protective effects against inflammatory and immune. Efforts are exerted in understanding the general mechanism and developing A2AAR selectively binding agonists. Using molecular dynamics (MD) simulations, we have studied the interactions between A2AAR and its agonist (adenosine), and analyzed the induced dynamic behaviors of the receptor. Key residues interacting with adenosine are identified: A632.61, I662.64, V843.32, L853.33, T883.36, F1685.29, M1775.38, L2496.51, H2506.52, and N2536.55 interacting with adenosine with affinities larger than 0.5 kcal/mol. Moreover, no interaction between adenosine and L1675.28 is observed, which supports our previous findings that L1675.28 is an antagonist specific binding reside. The dynamic behaviors of agonist bound A2AAR are found to be different from apo-A2AAR in three typical functional switches: (i) tight “ionic lock” forms in adenosine-A2AAR, but it is in equilibrium between formation and breakage in apo-A2AAR; (ii) the “rotamer toggle switch”, T883.36/F2426.44/W2466.48, adopted different rotameric conformations in adenosine-A2AAR and apo-A2AAR; (iii) adenosine-A2AAR has a flexible intracellular loop 2 (IC2) and α-helical IC3, while apo-A2AAR preferred α-helical IC2 and flexible IC3. Our results indicate that agonist binding induced different conformational rearrangements of these characteristic functional switches in adenosine-A2AAR and apo-A2AAR.