(La Jolla, CA). A team of researchers led by The Burnham Institute's Robert C. Liddington has determined the crystal structure of the binding complex between anthrax toxin and one of its host receptors. Inhalation anthrax, unless diagnosed at a very early stage, is fatal: there is no existing antidote once the toxin is blood borne. The studies published by Liddington and colleagues on-line in the July 4th issue of Nature offer new leads for the discovery of anthrax antitoxins that could be used in conjunction with antibiotics to treat late-stage anthrax. In a surprising twist, the new information will also help in the design of anthrax toxin as an anti-tumor agent for treatment of cancer.
Anthrax toxin is comprised of three proteins: protective antigen (PA), lethal factor (LF), and edema factor (EF). To gain entry into host cells, PA must recognize a receptor on the surface of the target cell. Once PA has bound to the cell, it then enables EF and LF to bind and form a pore through which PA forces EF and LF into the cell in a syringe-like action.
Liddington's laboratory, together with Stephen Leppla at the National Institute of Allergy and Infectious Diseases, studied the interaction of PA with the two known receptors for anthrax: TEM8 and CMG2. PA binds tightly to both receptors and can use either to transfer toxicity into the cell. They were able to determine the crystal structure of the PA-CMG2 binding complex at atomic resolution, which makes it possible to design small molecules that will interact with PA and prevent the binding complex from forming. Soluble forms of the receptors have indeed acted as decoys, distracting PA from binding both receptors.
The two receptors are similar in how they mediate entry into the cells, but differ in important ways: The CMG2 receptor is present in most tissues, whereas the TEM8 receptor is mostly found on the cells that form the blood vessel of tumors. This probably explains why anthrax toxin at sub-lethal doses has strong anti-tumor activity.
Indeed, Dr. Leppla is now developing anthrax toxin as an anti-tumor agent. Although the PA-TEM8 complex is yet to be solved, Liddington expects the interactions to be similar to that of the PA-CMG2 complex. "We can exploit the differences to design PA molecules that bind better to TEM8 than to CMG2," says Liddington, "which would minimize the side effects of toxin binding to normal tissues."
Liddington was recently awarded a $15 M grant from the National Institute of Allergy and Infectious Diseases that supports a multidisciplinary effort focused on developing candidate anti-toxins for anthrax and other potential agents of biological warfare.
Robert C. Liddington, Ph.D., is a member of The Burnham Institute's NCI-designated Cancer Center, and Director of the Institute's Program on Extracellular Matrix and Cell Adhesion. Eugenio Santelli, Ph.D. and Laurie A. Bankston, Ph.D., from Dr. Liddington's laboratory are co-authors on this study.
Stephen H. Leppla, Ph.D., is Chief of the Bacterial Toxins and Therapeutics Section at the National Institute of Allergy and Infectious Diseases, in Bethesda, MD.
This work was supported with funding from the National Institutes of Health and the Department of Defense.
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