title: Active-state model of a dopamine D2 receptor-Gαi complex stabilized by aripiprazole-type partial agonists.
abstract: Partial agonists exhibit a submaximal capacity to enhance the coupling of one receptor to an intracellular binding partner. Although a multitude of studies have reported different ligand-specific conformations for a given receptor, little is known about the mechanism by which different receptor conformations are connected to the capacity to activate the coupling to G-proteins. We have now performed molecular-dynamics simulations employing our recently described active-state homology model of the dopamine D2 receptor-Gαi protein-complex coupled to the partial agonists aripiprazole and FAUC350, in order to understand the structural determinants of partial agonism better. We have compared our findings with our model of the D2R-Gαi-complex in the presence of the full agonist dopamine. The two partial agonists are capable of inducing different conformations of important structural motifs, including the extracellular loop regions, the binding pocket and, in particular, intracellular G-protein-binding domains. As G-protein-coupling to certain intracellular epitopes of the receptor is considered the key step of allosterically triggered nucleotide-exchange, it is tempting to assume that impaired coupling between the receptor and the G-protein caused by distinct ligand-specific conformations is a major determinant of partial agonist efficacy.
authors.affiliation: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University, Erlangen, Germany; Department of Chemistry and Pharmacy, Computer Chemistry Center, Friedrich Alexander University, Erlangen, Germany.
authors.forename: Ralf C
authors.initials: RC
authors.lastname: Kling
authors.affiliation: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University, Erlangen, Germany.
authors.forename: Nuska
authors.initials: N
authors.lastname: Tschammer
authors.affiliation: Department of Chemistry and Pharmacy, Computer Chemistry Center, Friedrich Alexander University, Erlangen, Germany; Central Institute for Scientific Computing, Friedrich Alexander University, Erlangen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Lanig
authors.affiliation: Department of Chemistry and Pharmacy, Computer Chemistry Center, Friedrich Alexander University, Erlangen, Germany; Centre for Molecular Design, University of Portsmouth, King Henry Building, Portsmouth, United Kingdom.
authors.forename: Timothy
authors.initials: T
authors.lastname: Clark
authors.affiliation: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University, Erlangen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
mesh_terms: D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole; D004298:Dopamine / Q000378:metabolism*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D010879:Piperazines / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects*; D015363:Quinolones / Q000494:pharmacology*; D017448:Receptors, Dopamine D2 / Q000737:chemistry* / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D008024:Ligands; D010879:Piperazines; D015363:Quinolones; D017448:Receptors, Dopamine D2; D000068180:Aripiprazole; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D004298:Dopamine