Researchers have discovered the structural secret that allows an intestinal worm to live in the stomach without being digested. A protein thwarts pepsin, a key enzyme of the stomach, in a way never seen before. The trick, reported in the August issue of Nature Structural Biology, may lead to drugs against a host of infectious diseases, from malaria to AIDS.
The pepsin that helps you digest a burger is one of many aspartic proteinases, a family of proteins that chew up other proteins. The most notorious example of this class is HIV proteinase, commonly called HIV protease, which helps the virus cut a long polypeptide into functional proteins; it has become the target of several successful AIDS drugs. Aspartic proteinases are also used for various tasks by the parasites that cause malaria, African river blindness, and elephantiasis. In order to block proteinases, scientists have typically designed small decoy molecules that look like the enzymes' natural target but can't be cut.
This may not be the only possible approach, as nature has its own ways of blocking proteinases. A yeast inhibitor called IA-3, for example--the first aspartic proteinase inhibitor whose structure was determined by scientists--binds to a proteinase in a helical structure that the enzyme is unable to cleave. Looking for other natural tactics, a team led by structural biologist Michael James of the University of Alberta examined Ascaris suum, a worm that infects pigs. (A close cousin infects more than a billion humans.) Ascaris has a proteinase-inhibiting protein called PI-3, which the worm uses to prevent being digested by pepsin in the pig stomach. Using x-ray crystallography, the researchers found that as PI-3 blocks the active site of pepsin, it also puts a chokehold on a flap in the enzyme, preventing it from opening up and latching onto a protein. The mechanism is strikingly different from that of IA-3.
It's not clear whether this knowledge will help combat Ascaris infections, says biochemist Colin Berry of the Cardiff School of Biosciences in Wales; the worm may well be able to survive an attack on its proteinase inhibitor. The real value of the study is that it may point the way to new drugs that, like PI-3, distort the flaps in proteinases from a variety of pathogens, he says. The inhibitors' structures "give you insight into a different way of inhibiting aspartic proteinases," Berry says.
Related sites
MRC
Protein Group, University of Alberta
Aspartic
proteinase advanced tutorial
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