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.
Laboratory of Computational Chemistry and Biochemistry, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Stefano
S
Vanni
Marilisa
M
Neri
Ivano
I
Tavernelli
Ursula
U
Rothlisberger
D001224:Aspartic Acid; D056004:Molecular Dynamics Simulation; D055355:Opsins; D011487:Protein Conformation; D011522:Protons; D011941:Receptors, Adrenergic / Q000737:chemistry*; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry; D015398:Signal Transduction
D055355:Opsins; D011522:Protons; D011941:Receptors, Adrenergic; D043562:Receptors, G-Protein-Coupled; D001224:Aspartic Acid