3/20/2018 PDB-101: Anthrax Toxin

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Anthrax Toxin
Anthrax bacteria build a deadly three-part toxin

Anthrax is a household word, in spite of the fact that

anthrax is not a common disease. For humans, anthrax
is difficult to contract. It is not transmitted from person
to person--it is usually contracted when people come
into contact with infected animals or their products. But
recently, anthrax has gained the potential to be a major
threat through bioterrorism. It is an effective weapon
because it forms sturdy spores that may be stored for
years, that rapidly lead to lethal infections when
inhaled.

A Lethal Combination Components of anthrax toxin: protective antigen (left), edema

Anthrax is caused by an unusually large bacterium, factor (center), and lethal factor (right).

Bacillus anthracis. Once its spores lodge in the skin or Download high quality TIFF image 
in the lungs, it rapidly begins growth and produces a
deadly three-part toxin. These toxins are designed for
maximum lethality, and are frighteningly effective. Part of the toxin is a delivery mechanism that seeks out cells;
another part is a toxic enzyme that rapidly kills the cell. In anthrax toxin, there is one delivery molecule, termed
"protective antigen" because of its use in anthrax vaccines (shown on the left from PDB entry 1acc ). It delivers
the other two parts, edema factor and lethal factor (center and right, from PDB entries 1k90  and 1jky ), which
are the toxic components that attack cells.

Keeping Deadly Company

These types of multiple-part toxins are quite common in the bacterial world because they are exquisitely effective.
Many other examples, such as toxins from the bacteria that cause cholera and whooping cough, may be found in the
PDB. The delivery component specifically seeks out cell surfaces and inserts the toxic component where it can do
the most damage. The toxic component is far more effective than poisons like cyanide and arsenic. Those poisons
attack one-on-one, with a single cyanide molecule poisoning a single protein molecule. But toxic enzymes are
compact cell-killing machines. Once inside the cell, they hop from molecule to molecule, destroying each in turn.
These molecules are so effective that in some cases a single molecule can kill an entire cell.

Protective Antigen
The protective antigen is the delivery mechanism of
anthrax toxin. The bacteria secrete it as a single chain,
as shown on the left from PDB entry 1acc . The
protein then finds a cell surface and binds to it. A
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human protease on the surfaces of cells then clips off a

small piece, colored blue here, arming the mechanism.
It then combines with six other copies of the protein to
form a seven-sided ring, as seen on the right from PDB
entry 1tzo . This ring binds firmly to the cell surface
and is thought to extend loops into the membrane,
forming a pore. The other two parts of the toxin then
bind to the ring and are carried into the cell.

Assembly of anthrax protective antigen.

Download high quality TIFF image 

Lethal Factor and Edema Factor

The two toxic components of anthrax toxin are both
enzymes that attack the signalling functions of the cell.
Once they are delivered inside by the protective
antigen, they set to work. The edema factor (shown on
the left) is an adenyl cyclase enzyme. It takes ATP (in
green) and clips off two phosphates, reconnecting the
remaining one back in a small loop to form cyclic AMP.
Cyclic AMP is an important messenger in cells, often
used to relay messages that are sent by hormones.
For instance, a rise in cyclic AMP in response to
adrenaline can cause an increase in heart rate. Edema
factor floods the cell with cyclic AMP, destroying the
careful balance normally achieved by hormones.
Edema factor (left) bound to ATP (green) and calmodulin
(yellow), and lethal factor (right) with a peptide from MAPKK Lethal factor (shown on the right) attacks at another
(green). sensitive spot. It is a very specific protease that makes
a cut in several similar mitogen-activated protein
kinase kinases. In the illustration, a small segment of
this target is shown in green, bound in the active site of the toxin. These kinases are essential steps at the end of
another signalling pathway which is important in cell growth and proliferation. The lethal factor destroys this control
by disabling one key step in the chain of messsages.

Exploring the Structure

The edema factor is activated once it gets inside cells by binding to calmodulin, a protein that is very common in our
cells. The factor is shown before activation on the left in PDB entry 1k8t  and after activation on the right in PDB
entry 1jky . Notice how calmodulin, shown in yellow, opens up the edema factor, making the active site more
available. It also shifts the placement of two key loops, shown in purple. In the unactivated form, one of these loops

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hangs down away from the active site and the other is
disordered, as indicated by the purple dots on its right
side. In the activated form, these two loops hold ATP
tightly, forming part of the active site that will convert it
to cyclic AMP. You can explore these structures in
more detail by clicking on the accession codes and
picking one of the options for 3D viewing.

References
1. Dixon, T.C., Meselson, M., Guillemin, J. and Hanna, P.C. (1999): Anthrax. New England Journal of Medicine
341, pp. 815-826.
2. Inglesby, T.V., et al. (1999): Anthrax as a Biological Weapon. Journal of the American Medical Association
281, pp. 1735-1745.

April 2002, David Goodsell

doi:10.2210/rcsb_pdb/mom_2002_4

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