Active-State Models of Ternary GPCR Complexes: Determinants of Selective Receptor-G-Protein Coupling

Based on the recently described crystal structure of the beta(2) adrenergic receptor - G(s)-protein complex, we report the first molecular-dynamics simulations of ternary GPCR complexes designed to identify the selectivity determinants for receptor-G-protein binding. Long-term molecular dynamics simulations of agonist-bound beta 2AR-G alpha s and D2R-G alpha, complexes embedded in a hydrated bilayer environment and computational alanine-scanning mutagenesis identified distinct residues of the N-terminal region of intracellular loop 3 to be crucial for coupling selectivity. Within the G-protein, specific amino acids of the alpha 5-helix, the C-terminus of the G alpha-subunit and the regions around alpha N-beta 1 and alpha 4-beta 6 were found to determine receptor recognition. Knowledge of these determinants of receptor-G-protein binding selectivity is essential for designing drugs that target specific receptor/G-protein combinations.