New drug target for herpes viruses?
CAMBRIDGE, Mass. (March 8, 2007) — 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.
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