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ShareJuly 5, 2004 — Scientists have determined a three-dimensional (3-D) molecular image of how anthrax toxin enters human cells, giving scientists more potential targets for blocking the toxin, the lethal part of anthrax bacteria. The finding also points to a possible way to design anthrax toxin molecules that selectively attack tumor cells, as described in the journal Nature published online July 4. The study, funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, was led by Robert C. Liddington, Ph.D., of the Burnham Institute in La Jolla, CA.
"This elegant work provides important new leads for the development of novel antitoxins to protect people from anthrax, a dangerous and serious bioterror threat," says NIAID Director Anthony S. Fauci, M.D. "It also leads us closer to therapies that could save lives late in the disease when large amounts of toxin are present and antibiotics are less effective."
Using an intense X-ray beam to determine the position of atoms in a crystal form of the protein complex, a scientific team mapped the 3-D structure of one of the anthrax toxin's proteins docked to a human anthrax toxin receptor. Anthrax toxin uses a protein known as protective antigen to gain entry into human or animal cells. The protective antigen protein can bind either of two different cell receptors: CMG2 and TEM8. In this study, scientists solved the puzzle of the molecular structure of the protective antigen protein and CMG2 bound together.
Previously, different groups of scientists in separate studies had determined the 3-D structures of the anthrax protective antigen protein and the CMG2 receptor--but only when unbound from each other. The structure of the protective antigen protein-CMG2 receptor complex offers a more precise, finely detailed snapshot of a crucial step in the intricate molecular choreography that ushers anthrax toxin into cells. This detailed, 3-D image provides researchers clearer targets for shutting down this process. For researchers working on anthrax antitoxins, the new 3-D image is like having a roadmap that connects two cities rather than having only separate maps of the two cities.
The newly revealed structure also points to a potential new tumor treatment using a genetically modified anthrax toxin, Dr. Liddington says. The TEM8 cell receptor is commonly found in cells lining the blood vessels of tumors. Although the structure of the TEM8 receptor has not been determined, scientists expect it to be similar to that of the CMG2 receptor. "Computer modeling could enable us to design a version of the anthrax toxin that binds only to TEM8 and not to CMG2," he notes. Such a toxin would kill tumor cells while leaving ordinary cells unharmed.
NIAID is a component of the National Institutes of Health, an agency of the U.S. Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on transplantation and immune-related illnesses, including autoimmune disorders, asthma and allergies.
Reference: E Santelli et al. Crystal structure of a complex between anthrax toxin and its host cell receptor. Nature. DOI: 10.1038/nature02763.
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