Dynamic Role of the G Protein in Stabilizing the Active State of the Adenosine A2A Receptor

Agonist binding in the extracellular region of the G protein-coupled adenosine A2A receptor increases its affinity to the G proteins in the intracellular region, and vice versa. The structural basis for this effect is not evident from the crystal structures of A2AR in various conformational states since it stems from the receptor dynamics. Using atomistic molecular dynamics simulations on four different conformational states of the adenosine A2A receptor, we observed that the agonists show decreased ligand mobility, lower entropy of the extracellular loops in the active-intermediate state compared with the inactive state. In contrast, the entropy of the intracellular region increases to prime the receptor for coupling the G protein. Coupling of the G protein to A2AR shrinks the agonist binding site, making tighter receptor agonist contacts with an increase in the strength of allosteric communication compared with the active-intermediate state. These insights provide a strong basis for structure-based ligand design studies. [Display omitted] •GPCR conformation dynamics reveals the forward and backward allosteric mechanism•Agonist binding increases the entropy in the intracellular region of the GPCR•G protein binding shrinks the receptor-ligand contacts in the extracellular region•Increased allostery between G protein and agonist in the GPCR-G protein complex Lee et al. show that allosteric communication between the agonist binding site and G protein coupling site in GPCRs leads to enhanced agonist affinity. The agonist binding site shrinks dynamically when the G protein is bound to the receptor. Understanding GPCR allostery provides newer strategies to design selective ligands.