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

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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

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    Chien, E. Y. T., Liu, W., Zhao, Q., Katritch, V., Han, G. W., Hanson, M. A., Shi, L., Newman, A. H., Javitch, J. A., Cherezov, V., & 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