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 be
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NIH/National Institute of General Medical Sciences