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

Ellen Y T Chien, Wei Liu, Qiang Zhao, Vsevolod Katritch, Gye Won Han, Michael A. Hanson, Lei Shi, Amy Hauck Newman, Jonathan A. Javitch, Vadim Cherezov, Raymond C. Stevens

Research output: Contribution to journalArticle

824 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1091-1095
Number of pages5
JournalScience
Volume330
Issue number6007
DOIs
StatePublished - Nov 19 2010
Externally publishedYes

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eticlopride
Dopamine D3 Receptors
Dopamine
G-Protein-Coupled Receptors
Amides
Cognition
Substance-Related Disorders
Emotions
Binding Sites
Ligands
Brain

ASJC Scopus subject areas

  • General

Cite this

Chien, E. Y. T., Liu, W., Zhao, Q., Katritch, V., Han, G. W., Hanson, M. A., ... Stevens, R. C. (2010). Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science, 330(6007), 1091-1095. https://doi.org/10.1126/science.1197410

Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. / Chien, Ellen Y T; Liu, Wei; Zhao, Qiang; Katritch, Vsevolod; Han, Gye Won; Hanson, Michael A.; Shi, Lei; Newman, Amy Hauck; Javitch, Jonathan A.; Cherezov, Vadim; Stevens, Raymond C.

In: Science, Vol. 330, No. 6007, 19.11.2010, p. 1091-1095.

Research output: Contribution to journalArticle

Chien, EYT, Liu, W, Zhao, Q, Katritch, V, Han, GW, Hanson, MA, Shi, L, Newman, AH, Javitch, JA, Cherezov, V & Stevens, RC 2010, 'Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist', Science, vol. 330, no. 6007, pp. 1091-1095. https://doi.org/10.1126/science.1197410
Chien, Ellen Y T ; Liu, Wei ; Zhao, Qiang ; Katritch, Vsevolod ; Han, Gye Won ; Hanson, Michael A. ; Shi, Lei ; Newman, Amy Hauck ; Javitch, Jonathan A. ; Cherezov, Vadim ; Stevens, Raymond C. / Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. In: Science. 2010 ; Vol. 330, No. 6007. pp. 1091-1095.
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