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The painful truth: seeing is believing.

In a feat that would have been unachievable only a few years ago, the curtain on a protein informally known as the "wasabi receptor" has been pulled aside by researchers at the University of California, San Francisco, revealing at near-atomic resolution structures that could be targeted with anti-inflammatory pain drugs.

Officially named TRPA1 (pronounced "trip A1"), the newly visualized protein resides in the cellular membrane of sensory nerve cells. It detects certain chemical agents originating from outside of our bodies-pungent irritants found in substances ranging from wasabi to tear gas --but also is triggered by pain-inducing signals originating within, especially those that arise in response to tissue damage and inflammation.

"The pain system is there to warn us when we need to avoid things that can cause injury, but also to enhance protective mechanisms," says David Julius, professor and chair of the Department of Physiology. "We have known that TRPA1 is very important in sensing environmental irritants, inflammatory pain, and itch, and so knowing more about how TRPA1 works is important for understanding basic pain mechanisms. Of course, this information may also help guide the design of new analgesic drugs."

Julius and co-senior author Yifan Cheng, associate professor of biochemistry and biophysics, were able to capture images of TRPA1 that reveal its structure in three dimensions.

The team used an approach called electron cryo-microscopy (cryo-EM), an imaging technique in which proteins are bombarded with electrons at very low temperatures. Thanks to a number of innovative hardware and software advances, cryo-EM has undergone a "resolution revolution" in image quality over the past several years. Using these tools, the group imaged TRPA1 at a resolution of about four angstroms. By way of comparison, the thickness of a credit card is about 8,000,000 angstroms.

The determination of aTRP structure by cryo-EM "sent shockwaves through the field of structural biology," Cheng relates, as many researchers had dismissed the method as "blob-ology": until quite recently, cryo-EM's resolution--about 15 angstroms at best--was far too coarse to discern the subtleties of structure in molecules as small as TRP ion channels.

"We have had some idea what TRPA1 might look like, but there's something elegant and satisfying about obtaining a real look at the structure, because seeing really is believing," marvels Julius.

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Title Annotation:Cryo-Microscopy
Publication:USA Today (Magazine)
Geographic Code:1USA
Date:Oct 1, 2015
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