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Molecular image of genotoxin reveals how bacteria damage human DNA

might induce cell cycle arrest because it stops cells from being sloughed off in areas such as the intestines where bacteria seek to make a home.

"CDT may also act as an immunosuppressant," says Stebbins, "since the immune system requires cell division to respond to microbial infection."

There are nearly 10 different species of disease-causing bacteria that use CDT, including Salmonella typhi, a bacteria that causes typhoid fever; Haemophilus ducreyi, a bacteria that causes genital ulcers; Campylobacter jejuni, a common cause of food poisoning; certain strains of Escherichia coli that cause diarrhea, and a host of other pathogenic bacteria.

"More CDT-containing bacteria are discovered each year," says Stebbins, "Many of these bacteria cause very different kinds of diseases and colonize different tissues. But they all have CDT. To me, that argues that it's playing an important role."

Stebbins' structure of CDT visually confirms that this genotoxin is made up of three subunits, including one called CdtB that cleaves, or cuts, DNA.

According to Stebbins' model, the three-unit toxin contains a long, deep groove, a cluster of ring-shaped molecules, called the "aromatic patch," and a dangling protein tail that can block a key portion of the CdtB subunit that is necessary for DNA cleavage.

"We're not sure what the role of the cleavage-blocking protein tail is, but the structure helps us to understand how to interact with the active site of CdtB to impair its activity, which could give us some ideas for achieving the same thing with a drug molecule," said Stebbins.

Armed with an atomic model of a protein, scientists can program computers to screen virtual representations of millions of compounds to see if they have a good chance of interacting with the target. Compounds are narrowed down to a selected few, which are then tested to determine how well they interact with the drug target. By screening compounds by comput
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26-May-2004


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