by Alisa Machalek
April 2, 2003

Three toxic proteins are critical for the deadly effect of the now-familiar anthrax bacterium, Bacillus anthracis. One of these toxins, called protective antigen, allows the other anthrax toxins to enter cells. The second, lethal factor, destroys immune system cells that normally defend the body. This process releases inflammatory molecules that can cause sepsis-related shock and death. The third toxin, edema factor, causes potentially lethal swelling and fluid buildup in the body. By itself, edema factor can be deadly. It also makes lethal factor 10 to 100 times more potent.

Scientists already knew the shape and features of the anthrax protective antigen and lethal factor toxins. This year, by solving the structure of edema factor, Dr. Wei-Jen Tang of the University of Chicago completed the detailed, three-dimensional picture of the third and final piece of this deadly triumvirate. Edema factor is harmless until it binds to a molecule called calmodulin. The new study reveals that edema factor changes its shape dramatically when it binds to calmodulin, creating a pocket in which it carries out the chemical reactions responsible for its toxic effects.

Because it contains a deep, narrow pocket, the activated edema factor appears to be an ideal drug target. By designing a small molecule to clog this pocket, pharmaceutical scientists may be able to develop a drug to combat anthrax infection. Other bacterial diseases that rely on proteins similar to edema factor include whooping cough and a hospital-acquired infection caused by Pseudomonas aeruginosa. The structure of edema factor--which grew out of basic research on cell communication--will provide a good starting point for designing new drugs to treat these other diseases as well.