Sodium‐induced allosteric changes in D2 dopamine receptor local dynamics modulate ligand selectivity

Abstract

The basis of allostery in GPCRs and its implications for ligand recognition remain a mystery. While determining the source of large differences in measured ligand affinity reported for a mutant D2 dopamine receptor, we uncovered a unique and significant allosteric response to the physiological modulator sodium. This response is characterized by a sodium‐dependent enhanced affinity for ligands of a specific structural class having either agonist or antagonist functional properties. To explore possible mechanisms for our empirically‐derived results, the influence of sodium on D2 receptor dynamics was examined by computational analysis of the molecular normal modes of motion. This result revealed divergence in the component motions of the D2 receptor with and without sodium bound to the putative sodium binding regions. One particularly sensitive mode involved the concerted motions of the extracellular portions of transmembrane‐spanning domains, which when computed in the presence of sodium appeared to disrupt a favorable pi‐stacking interaction between TM2 and TM3 freeing an aromatic residue in the receptor model for favorable interactions with aromatic portions of the ligands increasing their affinity. This demonstrates how a sodium‐dependent change in dynamic properties can yield the experimentally observed allosteric phenomenon.Supported R01 MH063162 (JAS), P01 DA012923 and K05 DA00060 (HW).