GPCR A_2AAR Agonist Binding and Induced Conformation Changes of Functional Switches

Agonist binding of A_2A adenosine receptor (A_2AAR) shows protective effects against in-flammatory and immune. Efforts are exerted in understanding the general mechanism and developing A_2AAR selectively binding agonists. Using molecular dynamics (MD) simula-tions, we have studied the interactions between A_2AAR and its agonist (adenosine), and an-alyzed the induced dynamic behaviors of the receptor. Key residues interacting with adeno-sine are identified: A63^2.61,I66^2.64, V84^3.32, L85^3.33, T88^3.36, F168^5.29, M177^5.38, L249^6.51, H250^6.52, and N253^6.55 interacting with adenosine with affinities larger than 0.5 kcal/mol. Moreover, no interaction between adenosine and L167^5.28 is observed, which supports our previous findings that L167^5.28 is an antagonist specific binding reside. The dynamic be-haviors of agonist bound A_2AAR are found to be different from apo-A_2AAR in three typical functional switches: (i) tight “ionic lock” forms in adenosine-A_2AAR, but it is in equi-librium between formation and breakage in apo-A_2AAR; (ii) the “rotamer toggle switch”, T88^3.36/F242^6.44/W246^6.48, adopted different rotameric conformations in adenosine-A_2AAR and apo-A_2AAR; (iii) adenosine-A_2AAR has a flexible intracellular loop 2 (IC2) and ɑ-helical IC3, while apo-A_2AAR preferred ɑ-helical IC2 and flexible IC3. Our results indicate that agonist binding induced different conformational rearrangements of these characteristic func-tional switches in adenosine-A_2AAR and apo-A_2AAR.