Structure of the Human Dopamine D3 Receptor in Complex with a D2/D3 Selective Antagonist

TLDR

Dopamine regulates movement, cognition, and emotion through dopamine G protein‑coupled receptors in the brain. The study seeks to use these structural differences to guide the design of D3R‑selective agents for drug abuse and neuropsychiatric disorders. The crystal structure of human D3R bound to eticlopride reveals distinct extracellular and intracellular conformations, including a second binding pocket for the aryl amide of R‑22 that differs from D2R, providing insights for selective drug design.

Abstract

Dopamine modulates movement, cognition, and emotion through activation of dopamine G protein-coupled receptors in the brain. The crystal structure of the human dopamine D3 receptor (D3R) in complex with the small molecule D2R/D3R-specific antagonist eticlopride reveals important features of the ligand binding pocket and extracellular loops. On the intracellular side of the receptor, a locked conformation of the ionic lock and two distinctly different conformations of intracellular loop 2 are observed. Docking of R-22, a D3R-selective antagonist, reveals an extracellular extension of the eticlopride binding site that comprises a second binding pocket for the aryl amide of R-22, which differs between the highly homologous D2R and D3R. This difference provides direction to the design of D3R-selective agents for treating drug abuse and other neuropsychiatric indications.