Structure of the Human Dopamine D3 Receptor in Complex with a D2/D3 Selective Antagonist

doi:10.1126/science.1197410

Paper

Structure of the Human Dopamine D3 Receptor in Complex with a D2/D3 Selective Antagonist

Published Nov 19, 2010 · E. Chien, Wei Liu, Qiang Zhao

Science

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1,110

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64

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Abstract

Tweaking Dopamine Reception Dopamine modulates many cognitive and emotional functions of the human brain by activating G protein–coupled receptors. Antipsychotic drugs that block two of the receptor subtypes are used to treat schizophrenia but have multiple side effects. Chien et al. (p. 1091; see the Research Article by Wu et al.) resolved the crystal structure of one receptor in complex with a small-molecule inhibitor at 3.15 angstrom resolution. Homology modeling with other receptor subtypes might be a promising route to reveal potential structural differences that can be exploited in the design of selective therapeutic inhibitors having fewer side effects. Discovery of a binding site in the extracellular domain of a dopamine receptor offers hope for more selective therapeutics. 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.

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Study Snapshot

The crystal structure of the human dopamine D3 receptor in complex with eticlopride reveals structural differences that could lead to more selective therapeutic inhibitors with fewer side effects for treating drug abuse and other neuropsychiatric indications.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

Structure of the Human Dopamine D3 Receptor in Complex with a D2/D3 Selective Antagonist

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