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.

Structural mechanism of G protein activation by G protein-coupled receptor

“…Recent computer modeling studies adopted β2-adrenoceptor-Gs X-ray crystal structure to understand the G protein selectivity and the differential effect of ligands (Kling et al, 2014;Rose et al, 2014). Rose et al (2014) suggested that the selectivity between Gs and Gi may be determined by the bulkiness of the C-terminus of Gα and the degree of the outward movement of GPCR TM6.…”

“…Rose et al (2014) suggested that the selectivity between Gs and Gi may be determined by the bulkiness of the C-terminus of Gα and the degree of the outward movement of GPCR TM6. Another study with computer simulation tested the effect of functionally-different ligands on the conformation of dopamine D2 receptor-Gi complex (Kling et al, 2014). In the Kling et al study, the contact of the C-terminus of Gα with TM7/H8 hinge of dopamine D2 receptor is present with full agonist but absent with partial agonist.…”

Synthesis, Biological, and Computational Evaluation of Substituted 1‐(2‐Methoxyphenyl)‐4‐(1‐phenethylpiperidin‐4‐yl)piperazines and 1‐(2‐Methoxyphenyl)‐4‐[(1‐phenethylpiperidin‐4‐yl)methyl]piperazines as Dopaminergic Ligands

“…Affinity in itself toward D 2 DAR ( K i , Table ) does not tell us much about biological activity of the compounds; arylpiperazines can be acting as D 2 dopaminergic agonist, partial agonist or antagonist and can exert their effect through different signaling pathways . Prediction of biological activity for dopaminergic arylpiperazines in silico can be available soon because of the recent progress in the field . This similarly holds through for the prediction of ligand selectivity where, in this case, D 2 DAR versus D 3 DAR selectivity is of particular interest .…”

Multi-target dopamine D3 receptor modulators: Actionable knowledge for drug design from molecular dynamics and machine learning

“…H-bond networks involving conserved pairs of amino acids in positions 6.55, 7.35 and 5.43 have been subject of several studies on the D2-like dopamine receptors sub-family (D2, D3 and D4). In the homologous (78% sequence homology) dopamine D2 receptor (D2DR) in complex with agonists and partial agonists, [10][11][12][13] these interaction networks have been associated with low-energy patterns and functional bias. Three conserved functional serine residues on TM5, i.e., S192 5.42 , S193, 5.43 and S196 5.46 are crucial in the GPCR activation pathway that involves the formation of H-bonds between ligand, water, and receptor.…”