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Taming a protein with a nanostring

UCLA physicists have developed a new approach to protein engineering by using molecular strings to control chemical mechanisms. They demonstrated how an enzyme could be physically controlled by a nanodevice -- a molecular spring made of DNA -- attached to it. This could lead to "smart medicines that can be controlled."

UCLA physicists have developed a new approach to protein engineering by using molecular strings to control chemical mechanisms. They demonstrated how an enzyme could be physically controlled by a nanodevice -- a molecular spring made of DNA -- attached to it. In fact, they changed the structure of a protein mechanically without modifying its sequence of amino acids. This new way of modifying the behavior of some proteins could lead to "smart medicines that can be controlled." But read more...

Before going further, here is a quote from Brian Wang in his advanced nanotechnology blog, who wrote about this new approach last week in this post, and which summarizes very elegantly what the researchers have done.

The functioning of the enzyme is determined by its current shape and they have added springs which they control at the right spots to turn it on and off. It is like forcing a flower to bloom by taking hold of the petals and opening it up.

After this clever explanation in plain English, here is another quote about this research done by Giovanni Zocchi, UCLA associate professor of physics, and physics graduate student Brian Choi.

Zocchi and Choi report one representative example where the chemical mechanism by which the cell controls the function of its proteins can be effectively replaced, in vitro, by mechanical control. Specifically, they show how an enzyme complex called Protein Kinase A (PKA) -- which plays a fundamental role in the cell's signaling and metabolic pathways, and is controlled in the cell by a ubiquitous messenger molecule called cyclic AMP -- can instead be controlled mechanically by a nanodevice that the researchers attached to the enzyme complex.

The image below shows you how the molecular spring is taking control of the protein. "UCLA physicists controlled enzyme complex Protein Kinase A PKA’s regulatory subunit (green & red) through a molecular spring (light blue). Under tension (lower part) the spring leads to a change in the regulatory unit, causing the catalytic subunit (purple, left) to separate, activating the enzyme. (Credit for image and caption: Giovanni Zocchi/UCLA Physics). And here is a link to a larger version.

Taking control of a protein

"Molecular biologists have been trained for 50 years to think that because the sequence of amino acids determines a protein's structure and the structure determines its function, if you want to change the structure, the way to do so is to change the sequence of amino acids. While that approach is correct, it is not the only way. We are introducing the notion that you can keep the sequence but change the structure with mechanical forces.

And what could be the next step for these researchers?

"I want to see whether we can make molecules which kill a cell based on the genetic signature of the cell," Zocchi said. "Cancer cells would be an obvious application. This will however require many further steps." [...] "In the future, perhaps we can control more complicated molecular machines such as ribosomes. Many antibiotics work by blocking the ribosome of bacteria."

For more information, this research work has been published by the Journal of the American Chemical Society under the title "Mimicking cAMP-Dependent Allosteric Control of Protein Kinase A through Mechanical Tension" (June 8, 2006). Here is a link to the abstract

Sources: University of California - Los Angeles news release, via EurekAlert!, June 9, 2006; and various web sites

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