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Structure of a DNA attack
After two years and hundreds of gallons of buffering solution, scientists in C. Erec Stebbins’ laboratory have visualized the molecular structure of a genotoxin used by 10 different disease-causing bacteria to attack human DNA.
The image they obtained of the cytolethal distending toxin (CDT) (right) will help scientists understand the activity of this potential carcinogen and to design new drugs to fight a range of bacterial diseases that are caused when the toxin creates lesions and breaks that cause cells to stop dividing and die.
“More CDT-containing bacteria are discovered each year,” says Stebbins, head of the Laboratory of Structural Microbiology. “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 it 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 damage to the host cell genome.
“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,” says Stebbins.
Stebbins has solved the structures of over 10 other proteins, including the cancer-related VHL tumor-suppressor and several other bacterial toxins.

July 16, 2004



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