Structure of the Human Dopamine D3 Receptor in Complex with a D2/D3 Selective Antagonist
Top Cited Papers
- 19 November 2010
- journal article
- other
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 330 (6007), 1091-1095
- https://doi.org/10.1126/science.1197410
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.Keywords
This publication has 38 references indexed in Scilit:
- The Tetrahydroisoquinoline Derivative SB269,652 Is an Allosteric Antagonist at Dopamine D3 and D2 ReceptorsMolecular Pharmacology, 2010
- Current perspectives on selective dopamine D3 receptor antagonists as pharmacotherapeutics for addictions and related disordersAnnals of the New York Academy of Sciences, 2010
- N-(4-(4-(2,3-Dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides with Functionalized Linking Chains as High Affinity and Enantioselective D3 Receptor AntagonistsJournal of Medicinal Chemistry, 2009
- Identification of two distinct inactive conformations of the β 2 -adrenergic receptor reconciles structural and biochemical observationsProceedings of the National Academy of Sciences of the United States of America, 2009
- The 2.6 Angstrom Crystal Structure of a Human A 2A Adenosine Receptor Bound to an AntagonistScience, 2008
- Dopamine D2 receptors form higher order oligomers at physiological expression levelsThe EMBO Journal, 2008
- Structure of a β1-adrenergic G-protein-coupled receptorNature, 2008
- A Specific Cholesterol Binding Site Is Established by the 2.8 Å Structure of the Human β2-Adrenergic ReceptorStructure, 2008
- Stabilization of the Human β2-Adrenergic Receptor TM4–TM3–TM5 Helix Interface by Mutagenesis of Glu1223.41, A Critical Residue in GPCR StructureJournal of Molecular Biology, 2008
- High-Resolution Crystal Structure of an Engineered Human β 2 -Adrenergic G Protein–Coupled ReceptorScience, 2007