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Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist

Academic Article
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Overview

authors

  • Chien, E. Y. T.
  • Liu, W.
  • Zhao, Q. A.
  • Katritch, Vsevolod
  • Han, G. W.
  • Hanson, Michael
  • Shi, L.
  • Newman, A. H.
  • Javitch, J. A.
  • Cherezov, Vadim
  • Stevens, Raymond

publication date

  • November 2010

journal

  • Science  Journal

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.

subject areas

  • Animals
  • Arginine
  • Binding Sites
  • Cell Line
  • Crystallography, X-Ray
  • Dopamine Antagonists
  • Dopamine D2 Receptor Antagonists
  • Humans
  • Models, Molecular
  • Protein Conformation
  • Receptors, Dopamine D3
  • Recombinant Proteins
  • Salicylamides
  • Spodoptera
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Identity

PubMed Central ID

  • PMC3058422

International Standard Serial Number (ISSN)

  • 0036-8075

Digital Object Identifier (DOI)

  • 10.1126/science.1197410

PubMed ID

  • 21097933
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Additional Document Info

start page

  • 1091

end page

  • 1095

volume

  • 330

issue

  • 6007

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