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

By analyzing and simulating inactive conformations of the highly homologous dopamine D(2) and D(3) receptors (D(2)R and D(3)R), we find that eticlopride binds D(2)R in a pose very similar to that in the D(3)R/eticlopride structure but incompatible with the D(2)R/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 D(2)R/risperidone structure to an extended conformation similar to that in the D(3)R/eticlopride structure. Our results reveal previously unappreciated diversity and dynamics in the inactive conformations of D(2)R. These findings are critical for rational drug discovery, as limiting a virtual screen to a single conformation will miss relevant ligands.