Journal
SCIENCE
Volume 330, Issue 6007, Pages 1091-1095Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1197410
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Funding
- Protein Structure Initiative (PSI) [U54 GM074961, U54 GM094618]
- NIH Roadmap [P50 GM073197]
- NIH [R21 RR025336, GM075915]
- Pfizer
- National Institute on Drug Abuse [DA022413, MH54137, DA023694]
- National Science Foundation [IIS0308078]
- Science Foundation Ireland [02-IN1-B266]
- National Cancer Institute [Y1-CO-1020]
- National Institute of General Medical Sciences [Y1-GM-1104]
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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.
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