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November 18, 2010

Dopamine Show-And-Tell

Structural Biology: First close-up of a dopamine receptor could aid drug discovery

Carmen Drahl

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Reaching Out: In a computer model, the less selective dopamine receptor blocker eticlopride (peach) binds solely at the dopamine-binding site, but a more selective blocker (yellow) spans another pocket as well. Adapted from Science
Reaching Out In a computer model, the less selective dopamine receptor blocker eticlopride (peach) binds solely at the dopamine-binding site, but a more selective blocker (yellow) spans another pocket as well.

For the first time, researchers have determined the structure of a receptor that responds to the neurotransmitter dopamine. The structure could aid the hunt for new drugs targeting dopamine receptors for diseases such as substance abuse or schizophrenia.

Dopamine has a hand in everyday brain activities from memory to movement. It exerts its effects through a set of proteins classified as G-protein-coupled receptors (GPCR), which each snake across cell membranes seven times. Early medications for schizophrenia blocked several different dopamine receptor subtypes at once, but they led to movement disorders and other side effects. To reduce side effects, chemists have made more selective blockers, but these have yet to see success as drugs.

To better understand this class of receptors, Raymond C. Stevens and staff scientist Ellen Y. T. Chien of Scripps Research Institute, Jonathan A. Javitch of Columbia University, and colleagues determined the X-ray crystal structure of a human dopamine receptor called D3 bound to a small-molecule blocker called eticlopride (Science, DOI: 10.1126/science.1197410). From that structure, they built a computational model that highlights subtle differences between D3 and a related dopamine receptor called D2. In their model, a blocker selective for D3 binds in two pockets—the dopamine-binding site and another pocket right next door. "D2 doesn't have that second pocket, so you can now think about tuning selectivity for D3 only," Stevens says.

The dopamine receptor structure is one of just a handful of GPCR structures that have been determined. Just last month, Stevens' team reported the structure of another GPCR, the CXCR4 chemokine receptor (Science, DOI: 10.1126/science.1194396).

Obtaining GPCR structures "is still a very challenging area of structural biology," says membrane protein biochemist Brian K. Kobilka of Stanford University School of Medicine. Each GPCR has distinctive functional properties, he says. "So we're going to need lots more structures to figure out how these receptors really work."

Chemical & Engineering News
ISSN 0009-2347
Copyright © 2011 American Chemical Society
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