title: Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist.
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.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Ellen Y T
authors.initials: EY
authors.lastname: Chien
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhao
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Katritch
authors.forename: Gye Won
authors.initials: GW
authors.lastname: Han
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hanson
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: Amy Hauck
authors.initials: AH
authors.lastname: Newman
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Javitch
authors.forename: Vadim
authors.initials: V
authors.lastname: Cherezov
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
mesh_terms: D000818:Animals; D001120:Arginine / Q000737:chemistry; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D018492:Dopamine Antagonists / Q000737:chemistry*; D065127:Dopamine D2 Receptor Antagonists; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry; D012457:Salicylamides / Q000737:chemistry*; D018411:Spodoptera
chemical_list: D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D050637:Receptors, Dopamine D3; D011994:Recombinant Proteins; D012457:Salicylamides; D001120:Arginine; C045989:eticlopride