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, w

SUBMITTER: Lane JR 

PROVIDER: S-EPMC7053997 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature