3D structure of anthrax toxin complex solved
toxin as it binds to and enters human cells could lead to both a
treatment for the disease and a way to harness its effects in
cancer therapy, according to a report in the journal Nature.
The three-dimensional molecular image of the anthrax toxin complex could unveil areas of the molecule that could be targeted by blocking molecules, according to the researchers, led by Robert Liddington of the Burnham Institute in California, US.
Anthrax, caused by the bacterium Bacillus anthracis, is an extremely rare disease but one which has come to the fore because of its potential use as a biological warfare or terrorism weapon. In the wake of the terrorist attacks on the World Trade Centre on 11 September 2001, a number of cases of anthrax sent through the mail re-invigorated efforts to find new means of protecting people from the disease.
A vaccine against anthrax has been available since the 1950s, but its use is generally reserved for military personnel and it has been controversially linked to so-called Gulf war syndrome, a disease that affected soldiers who took part in the first war in Iraq. New anthrax vaccines are in the pipeline, but have yet to prove themselves in clinical trials.
Meanwhile, some cases of anthrax can be treated with antibiotics, but if a patient inhales anthrax spores the infection can often be too far advanced at detection to respond to treatment.
Using X-ray crystallography, a scientific team mapped the 3D 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 3D 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.
The finding also points to a possible way to design anthrax toxin molecules that selectively attack tumour cells.
The director of the National Institute for Allergy and Infectious Diseases in the US, Anthony Fauci, said that the discovery "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."
The newly revealed structure also points to a potential new tumour treatment using a genetically modified anthrax toxin, Liddington said. The TEM8 cell receptor is commonly found in cells lining the blood vessels of tumours. Although the structure of the receptor has not been determined, scientists expect it to be similar to that of the CMG2 receptor.
"Computer modelling could enable us to design a version of the anthrax toxin that binds only to TEM8 and not to CMG2," he noted. Such a toxin would kill cancer cells while leaving ordinary cells unharmed.
