|
Mutations in p300/CBP are linked to a variety of cancers, including
those of the colon, breast, pancreas, and prostate. Researchers
believe that a substance that selectively inhibits p300/CBP might be
the basis for an anticancer agent.
Nearly 10 years ago, Cole and his coworkers designed a p300/CBP
inhibitor. But the inhibitor is not active in the human body, so it
has been used exclusively as a research tool.
In the new study, the investigators combined X-ray crystallography
with detailed enzymology to understand how p300/CBP works.
Their three-dimensional crystal structure provides an image of how a
key part of p300/CBP binds to the inhibitor. Their studies of numerous
mutant versions of the enzyme reveal which amino acids in p300/CBP are
essential for its activity.
The work has a number of clinical implications. Understanding the
structure and behavior of p300/CBP will help scientists design a p300/CBP
inhibitor that might function in human cells as an anticancer drug.
Proper functioning of p300/CBP is critical for insulin regulation and
the health of heart cells. As a result, compounds that can regulate
p300/CBP activity might be useful in the treatment of diabetes and
heart disease.
In addition, HAT activity is necessary for the multiplication of HIV,
leading at least one scientific group to suggest that targeting HATs
or similar enzymes might be an new way to thwart the virus.
Finally, the article also shows that some p300/CBP mutations
previously linked to certain cancers lie right where p300/CBP contacts
the inhibitor. Studying how these mutations alter the enzyme's
function should shed light on why the mutations can lead to disease.
"This work illustrates how enzymology and structural biology can
combine to yield both fundamental and practical insights about an
important biomedical problem. The studies provide a new framework for
understanding p300/CBP in health and disease," said Jeremy M. Berg,
NIGMS Director.
|
