ABSTRACT
SB269652 is to our knowledge the first drug-like allosteric modulator of the dopamine D2 receptor (D2R), but it contains structural features associated with orthosteric D2R antagonists. Using a functional complementation system to control the identity of individual protomers within a dimeric D2R complex, we converted the pharmacology of the interaction between SB269652 and dopamine from allosteric to competitive by impairing ligand binding to one of the protomers, indicating that the allostery requires D2R dimers. Additional experiments identified a 'bitopic' pose for SB269652 extending from the orthosteric site into a secondary pocket at the extracellular end of the transmembrane (TM) domain, involving TM2 and TM7. Engagement of this secondary pocket was a requirement for the allosteric pharmacology of SB269652. This suggests a new mechanism whereby a bitopic ligand binds in an extended pose on one G protein-coupled receptor protomer to allosterically modulate the binding of a ligand to the orthosteric site of a second protomer.
