title: Active-state models of ternary GPCR complexes: determinants of selective receptor-G-protein coupling.
abstract: Based on the recently described crystal structure of the β2 adrenergic receptor--Gs-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 β2AR-Gαs and D2R-Gαi 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 α5-helix, the C-terminus of the Gα-subunit and the regions around αN-β1 and α4-β6 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.
authors.affiliation: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University, Erlangen, Germany.
authors.forename: Ralf C
authors.initials: RC
authors.lastname: Kling
authors.forename: Harald
authors.initials: H
authors.lastname: Lanig
authors.forename: Timothy
authors.initials: T
authors.lastname: Clark
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
mesh_terms: D000409:Alanine / Q000235:genetics; D000595:Amino Acid Sequence; D001665:Binding Sites; D004298:Dopamine / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000737:chemistry / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006639:Histidine / Q000378:metabolism; D008024:Ligands; D008954:Models, Biological; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism*; D016296:Mutagenesis; D017433:Protein Structure, Secondary; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry / Q000378:metabolism; D011954:Receptors, Dopamine / Q000737:chemistry / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D040681:Structural Homology, Protein
chemical_list: D008024:Ligands; D046912:Multiprotein Complexes; D018343:Receptors, Adrenergic, beta-2; D011954:Receptors, Dopamine; D043562:Receptors, G-Protein-Coupled; D006639:Histidine; D019204:GTP-Binding Proteins; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000409:Alanine; D004298:Dopamine