October 29, 2001
Volume 79, Number 44
CENEAR 79 44 p. 9
ISSN 0009-2347
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Better understanding of the toxin will yield new treatments, researchers hope


The search for new anthrax treatments is bolstered by two recent findings that could help in the design of drugs to neutralize anthrax toxin. One study has identified the toxin's cellular receptor. The other describes the structure of one of the toxin's components. The findings will be published in the Nov. 8 issue of Nature; they are now available at

The recent spate of anthrax spore deliveries by mail has triggered a run on the antibiotic Cipro. But drugs targeting the toxin itself are needed. Often, inhalation anthrax is diagnosed only after a victim's bacterial count has soared. Although antibiotics can wipe out the bacteria, they can do nothing to clear the toxin already present in lethal amounts. Furthermore, antitoxin drugs, unlike antibiotics, would not be prey to bacterial mechanisms for developing resistance.

Anthrax toxin consists of three proteins. One protein, called protective antigen, binds to a cell receptor and facilitates the entry into the cell of the other two, which are enzymes that impair the body's defense mechanisms. Although secreted together, the three float in the bloodstream separately and then reunite on the cell surface. Earlier, preventing that reunion was proposed as a therapeutic approach by R. John Collier at Harvard Medical School and others (C&EN, Oct. 8, page 12).

Now, the receptor for protective antigen has been identified by a team led by Collier and John A. T. Young at the University of Wisconsin, Madison.

The receptor spans the cell membrane once, Young says. The extracellular side contains a small motif--called von Willebrand factor A domain--to which protective antigen binds.

On its own in solution, this segment protects cells exposed to anthrax toxin. "It acts like a decoy, tying up protective antigen so that it does not bind to the cell surface, where it can cause damage," Young tells C&EN. "It is potentially therapeutic if used in sufficient amounts, but we haven't tested it yet on animal models. All we've done so far is protect cells growing in a dish."

Collier's lab is working to get enough receptor protein for a crystal structure. But even without a crystal structure, identification of the receptor now allows pharmaceutical companies to begin screening for small molecules that can disrupt the binding of protective antigen to the cell surface or that are better decoys than the soluble binding domain.

Meanwhile, Robert C. Liddington at the Burnham Institute, La Jolla, Calif., and collaborators have solved the crystal structure of the anthrax toxin component called lethal factor. This protein disrupts a signaling pathway involved in the release of defensive proteins.

Lethal factor exerts its effect by recognizing a signaling molecule, the kinase MAPKK-2. This molecule uses a tail at its N-terminus to dock onto another kinase in the signaling pathway. Lethal factor clips this tail, cutting communication between the two kinases. J. Eric Gouaux, an assistant professor of biochemistry and molecular biophysics at Columbia University, says the crystal structure shows how lethal factor recognizes and cleaves the target peptide.

"The work provides critical new insights into the mechanism of action of anthrax lethal factor," Gouaux says. "A high-resolution map of lethal factor will greatly assist the development of potent inhibitors that may prove to be life-saving drugs."

CLOSE-UP In the active site of lethal factor, zinc (purple) is coordinated to three protein side chains (His686, His690, and Glu735) and a water molecule that is hydrogen-bonded to glutamic acid (Glu687). The N-terminus of the natural substrate, MAPKK-2 (green), and a model of the substrate prior to peptide cleavage (yellow, blue, and red) are shown. A rotation prior to cleavage moves Pro10 of MAPKK-2 into the substrate-binding pocket (S1), bringing it near zinc-bound water.

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