3-D Structure of Anthrax Toxin Complex Solved
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,
"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.
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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. Press releases, fact sheets and other NIAID-related
materials are available on the NIAID Web site at http://www.niaid.nih.gov.
Reference: E Santelli et al. Crystal structure of a complex between
anthrax toxin and its host cell receptor. Nature. DOI: 10.1038/nature02763.