Allosteric Communication Pathways in G-Protein-Coupled Receptors

G protein coupled receptors (GPCRs) are membrane proteins that allosterically transduce the signal of ligand binding in the extracellular (EC) domain to couple to proteins in the intracellular (IC) domain. However the complete pathway of allosteric communication from the EC to the IC domain, including the role of individual amino acids in mediating the pathway is not known. Using mutual information calculated from microseconds long molecular dynamics simulations, we have elucidated the allosteric pathways in three different conformational states of β2-adrenergic receptor (β2AR): 1) inverse-agonist bound inactive state, 2) agonist bound intermediate state and 3) agonist and G-protein bound fully active state. The inactive state is less dynamic compared to the intermediate and active states. The allosteric pipelines from the EC domain to the IC domain are weakened in the agonist bound intermediate state, thus decoupling the EC domain from the IC domain, and making the receptor more dynamic compared to the other states. We also performed extensive analysis of the allosteric pipelines in the inactive state of all six biogenic amine receptors (muscarinic receptors, dopamine receptor, adrenergic receptors and histamine receptor). All the six biogenic amine GPCRs show several conserved and common allosteric communication pipelines from the residues in the agonist binding site with those in the G protein interface. Residues along these pipelines serve as major hubs of allosteric communication with the G protein, since their mutations either deactivate or increase the basal activity of the receptors. These findings have important implications in understanding the dynamics and allosteric mechanism of communication in class A GPCRs and hence useful for designing conformation specific drugs.