The structure of an enzyme has been discovered by researchers, which could help in understanding the mutations in the enzyme that could lead to diseases like cancer and diabetes.
This knowledge of the structure of this enzyme, called p300/CBP, may have future implications in designing drugs for the treatment of cancer, diabetes, HIV, and heart disease.
The study led by 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, targeted on p300/CBP, belonging to a family of enzymes known as histone acetyltransferases, or HATs.
These enzymes work by activating the genes by attaching chemicals called acetyl groups to histones, the spool-like proteins that hold DNA in a tightly wound form. p300/CBP mutations are closely associated with a variety of cancers, including those of the colon, breast, pancreas, and prostate.
According to the researchers, a substance that selectively inhibits p300/CBP could be responsible for an anticancer agent.
In a study, almost 10 years ago the researchers designed a p300/CBP inhibitor. However, this inhibitor is not active in the human body, and that's why it has been used solely as a research tool.
For the new study, X-ray crystallography was combined with detailed enzymology to comprehend the working of p300/CBP. The researchers' three-dimensional crystal structure offers an image of how a key part of p300/CBP binds to the inhibitor. And which amino acids in p300/CBP are essential for its activity has been revealed through studies of numerous mutant versions of the enzyme.
This work has many clinical implications: it is possible for the scientists to design a p300/CBP inhibitor that might function in human cells as an anticancer drug by understanding the structure and behaviour of p300/CBP. The enzyme's proper functioning is essential for insulin regulation and the health of heart cells. Thus, compounds that are capable of regulating the activity of p300/CBP might help in the treatment of diabetes and heart disease.
Besides, the activity of HAT is necessary for the HIV multiplication, which ahs made at least one scientific group to suggest that targeting HATs or similar enzymes might be a new way to prevent the virus.
Ultimately, the study also demonstrates that some p300/CBP mutations previously linked to certain cancers are positioned right where p300/CBP contacts the inhibitor. The study of how these mutations alter the enzyme's function should explain why the mutations can lead to disease.
The research appears in the latest issue of the journal Nature.