Distinct inactive conformations of the dopamine D2 and D3 receptors correspond to different extents of inverse agonism

Abstract

By analyzing and simulating inactive conformations of the highly homologous dopamine D2 and D3 receptors (D2R and D3R), we find that eticlopride binds D2R in a pose very similar to that in the D3R/eticlopride structure but incompatible with the D2R/risperidone structure. In addition, risperidone occupies a sub-pocket near the Na+ binding site, whereas eticlopride does not. Based on these findings and our experimental results, we propose that the divergent receptor conformations stabilized by Na+-sensitive eticlopride and Na+-insensitive risperidone correspond to different degrees of inverse agonism. Moreover, our simulations reveal that the extracellular loops are highly dynamic, with spontaneous transitions of extracellular loop 2 from the helical conformation in the D2R/risperidone structure to an extended conformation similar to that in the D3R/eticlopride structure. Our results reveal previously unappreciated diversity and dynamics in the inactive conformations of D2R. These findings are critical for rational drug discovery, as limiting a virtual screen to a single conformation will miss relevant ligands.

Controlling receptor function from the extracellular vestibule of G-protein coupled receptors

“…2,[21][22][23] Likewise, mutation of Trp100 ECL1 Ala increases the association and dissociation of antagonist ligand risperidone. 24 The hD3 simulations lead to a very similar result (Fig. S2b, ESI †).…”

Structure of the dopamine D2 receptor in complex with the antipsychotic drug spiperone

“…Indeed, ECL2 in 5-HT 2A R moves slightly to bind a different ligand 26 . An MD simulation study also suggested these dynamics of the ECL2 of D 2 R 47 and reported that the helical conformation of ECL2 observed in D 2 R ris tended to unwind toward an extended conformation, similar to that of D 3 R eti , regardless of the bound ligand, including spiperone, risperidone, or eticlopride 47 . The unwinding involves a drastic rearrangement of the side chain of Ile183 45.51 , dissociating from a hydrophobic pocket.…”

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

“…Thus no main difference was expected. In reality the results show differences in D2 inactive conformation that suggest different receptor inactive states ( Lane et al., 2020 ). In addition the agonist binding pocket in the D2 allows an extension that has been used to study D2 > D3 and D4 selectivity (with agonist ligands) and to determine the possibility to obtain biased agonists for D2 ( Fan et al., 2020 ).…”