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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.

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