A conserved protonation-induced switch can trigger "ionic-lock" formation in adrenergic receptors.

The mechanism of signal transduction in G-protein-coupled receptors (GPCRs) is a crucial step in cell signaling. However, the molecular details of this process are still largely undetermined. Carrying out submicrosecond molecular dynamics simulations of beta-adrenergic receptors, we found that cooperation between a number of highly conserved residues is crucial to alter the equilibrium between the active state and the inactive state of diffusible ligand GPCRs. In particular, "ionic-lock" formation in beta-adrenergic receptors is directly correlated with the protonation state of a highly conserved aspartic acid residue [Asp(2.50)] even though the two sites are located more than 20 A away from each other. Internal polar residues, acting as local microswitches, cooperate to propagate the signal from Asp(2.50) to the G-protein interaction site at the helix III-helix VI interface. Evolutionarily conserved differences between opsin and non-opsin GPCRs in the surrounding of Asp(2.50) influence the acidity of this residue and can thus help in rationalizing the differences in constitutive activity of class A GPCRs.

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