Winter 2005 |
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Commandeering Cellular Machinery Researchers manipulate recognition mechanism to detect small molecules. by John Toon |
RESEARCHERS HAVE LEARNED how to commandeer the complex machinery that cells use to recognize and respond to such important molecules as steroid hormones, thyroid hormones and vitamin D.
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The development could provide a foundation for a new family of biologically based mechanisms able to detect common drugs, chemical weapons and other small molecules. By allowing manipulation of this cellular protein machinery – known as nuclear receptors – the technique could also lead to new methods for producing enzymes and important pharmaceutical compounds.
“We are hijacking these nuclear receptors for a new set of purposes,” explains Donald Doyle, an assistant professor in the School of Chemistry and Biochemistry at the Georgia Institute of Technology. “We want to change the nuclear receptors themselves so they don’t recognize what they normally recognize, and instead recognize the small molecules we want to detect. That would allow us to develop a new type of sensing mechanism.”
A paper published in the Sept. 27, 2004, issue of the journal Proceedings of the National Academy of Sciences describes how Doyle’s research team – which also included Lauren Schwimmer, Priyanka Rohatgi, Bahareh Azizi and Katherine Seley – modified one type of nuclear receptor to bind a drug compound to which it previously did not respond. Based on this success, the researchers hope to demonstrate broader application with other small molecules.
The work was sponsored by the Research Corporation, the Seaver Foundation and the National Science Foundation.
Nuclear receptors are ligand-activated transcription factors contained in cells. When activated by specific small molecules, the nuclear receptors initiate a complex process that results in gene expression. Because these receptors play a vital role in controlling cellular response to these small molecules, scientists have been attempting to understand them and solve their molecular structures – with a goal of creating pharmaceuticals able to turn them off or on. The research often involves placing nuclear receptors into yeast cells, which because they do not have nuclear receptors of their own, allow scientists to isolate the activities of specific receptors.
“Now we have to see how far we can push this and how many small molecules we can accommodate with this technique,” Doyle says. “We are trying to generalize this approach to genetic selection. There is a lot of diversity we can work with in terms of different binding pockets and shapes, so this is only the first step.”
To read more, see gtresearchnews.gatech.edu/newsrelease/receptor.htm
For more information, contact Donald Doyle at 404-385-0631 or donald.doyle@chemistry.gatech.edu
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Last updated: April 3, 2005