New drug target for herpes viruses

Scientists in the lab of Whitehead Institute Member Hidde Ploegh and the Harvard University lab of Rachelle Gaudet have solved the complex structure of a recently discovered protein that is found in a wide range of herpes viruses. This protein may prove to be a potential drug target.

The protein, called UL36, was first identified in 2005 using a technique call a "activity-based profiling." In this procedure, applied in the Ploegh lab to a class of enzymes called ubiquitin-specific proteases, researchers use a molecular "bait" that will attract other proteins capable of binding to it. Ploegh likens this technique to fishing, in that while you have a general idea of what your bait might yield, you often catch something unexpected.

"Unlike most bioinformatics platforms, which rely on information already present in databases, this technique allows you to find completely novel proteins based on their ability to recognize the bait," says Ploegh, who is also a professor of biology at MIT.

UL36 proved to be such a molecule. When it was found in 2005 in cells infected with human herpes virus-1, there was no record of its activity in the scientific literature. Due to the nature of the probe used, the researchers reasoned that the newly identified target molecule may belong to a class of proteins whose function is to remove ubiquitin, a small molecule that flags proteins for disposal.

"This was surprising, since viruses in the herpes family were not known to have this type of ubiquitin-related activity," says Ploegh.

Reporting in the March 9 issue of the journal Molecular Cell, Whitehead postdoctoral researcher Christian Schlieker, in collaboration with Wilhelm Weihofen from the Gaudet lab, described the use of X-ray crystallography to delineate the intricate structure of M48, a close relative of UL36 that is found in murine cytomegalovirus, also a member of the herpesvirus family. Schlieker identified the precise area of the protein that removes ubiquitin from other molecules. These results revealed that the architecture of this enzyme is unique when compared to host enzymes that carry out similar tasks.

"We still don't know why the virus needs this particular function, but because all herpes viruses contain an activity very much like M48, it must be important," says Schlieker. "The fact that the enzyme's architecture is distinct from host proteins makes it an attractive target for therapeutic intervention."

The researchers are investigating possible functions for M48 in both cell cultures and animal models. Preliminary data suggest that M48 may enable the virus to evade the host immune system.

This research was supported by the National Institutes of Health and the U.S. Department of Energy.