Enzyme Structure Reveals New Drug Targets for Cancer and Other Diseases
If the genome is the parts list of the human cell, certain proteins
are the production managers, activating and deactivating genes
as needed. Scientists funded by the National Institute of General
Medical Sciences (NIGMS), part of the National Institutes of Health,
now have a clearer understanding of how a key protein controls
gene activity and how mutations in the protein may cause disease.
The work could provide new avenues to design drugs aimed at cancer,
diabetes, HIV, and heart disease.
The research appears in the Feb. 14, 2008, issue of the journal Nature.
The lead authors include Philip Cole, M.D., Ph.D., of the Johns
Hopkins University School of Medicine in Baltimore, Md., and Ronen
Marmorstein, Ph.D., of the Wistar Institute in Philadelphia, Pa.
The investigators focused on a protein called p300/CBP that belongs
to a family of enzymes known as histone acetyltransferases, or
HATs. These enzymes activate genes by attaching chemicals called
acetyl groups to histones, the spool-like proteins that hold DNA
in a tightly wound form.
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.
NIGMS (http://www.nigms.nih.gov)
supports basic biomedical research that is the foundation for advances
in disease diagnosis, treatment, and prevention.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.
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