Identification of a Lipid-Exposed Extrahelical Binding Site for Positive Allosteric Modulators of the Dopamine D2 Receptor

ACS Chem Neurosci. 2025 May 15. doi: 10.1021/acschemneuro.5c00105. Online ahead of print.

ABSTRACT

Recently, the first small-molecule positive allosteric modulators (PAMs) of the dopamine D₂ receptor (D₂R) were identified. The more potent PAM potentiated the effects of D₂R signaling in vitro and in an in vivo model predictive of anti-Parkinson’s efficacy. We reveal, based on the results of our site-directed mutagenesis and molecular dynamics experiments, that this scaffold binds to a hitherto unexploited lipid-exposed extrahelical allosteric site in the D₂R that lies in a cleft toward the intracellular aspect of the D₂R defined by residues in transmembrane domains 1 and 7 and helix 8. By binding to this site, the PAM acts to potentiate the binding affinity of efficacious agonists, such as dopamine. Our simulations suggest that the PAM achieves this effect by stabilizing an active-like conformation of the receptor, similar to the G protein-bound state with TM5 and the tyrosine toggle switch playing the major role.

PMID:40372152 | DOI:10.1021/acschemneuro.5c00105