The three dimensional structure and function of a gene regulator that is associated with some of the deadliest cancers has been unravelled by researchers at the Wistar Institute and the Johns Hopkins University School of Medicine.
The new findings on a key HAT (histone acetyltransferase) enzyme called p300/CBP attain significance as they may lead to the development of new cancer therapies.
Unlike most HAT enzymes that regulate the expression of only a few genes, p300/CBP is involved in the activation of a wide variety of genes, says the research team.
Besides, aberrant p300/CBP activity contributes to pancreatic, colon, and lung cancers as well as gastric and thyroid cancer and some leukemias. In addition to acting as an oncoprotein by promoting tumours, p300/CBP also can suppress tumours.
Ronen Marmorstein, a professor in the Gene Expression and Regulation Program at Wistar, says that such unusual properties have made this gene a target for developing new anti-cancer drugs.
"It's unusual to have a HAT that's so implicated in cancer, and even more unusual to have one that has both tumor suppressor and oncoprotein activities," Nature magazine quoted Marmorstein, who is also a senior author on the study, as saying.
The researchers used x-ray crystallography ó a widely used analytical technique in which x-rays are beamed at crystals containing the protein of interest ó to study crystals of p300/CBP.
Based on their analysis of the pattern of x-ray diffraction caused by the arrangement of atoms in the protein crystal, the research team deduced the three-dimensional structure of the crystallized protein.
Marmorstein says that studies of the structure show that p300/CBP contains a binding pocket that is suitable for associating with a wide range of substrates, the molecules it binds with, and makes p300/CBP more "promiscuous" than other HATs.
The researcher has revealed that p300/CBP also uses a novel "hit-and-run" chemical mechanism to convert its substrates to the resulting protein products. The chemical mechanism differs from those employed by other HATs in that the histone substrate binds only transiently, leaving after a very brief encounter, he adds.
Marmorstein says that this hit-and-run mechanism is consistent with the enzyme's ability to acetylate a variety of substrates because they don't have to bind in a very stable fashion.
According to him, the chemical mechanism employed by p300/CBP also bodes well for designing cancer drugs capable of pinpointing p300/CBP without affecting other enzymes, and causing unwanted side effects.
"Because of p300/CBP's chemical mechanism, which differs from that of other HATs, an inhibitor that works against this family of enzymes likely won't work against the other ones," Marmorstein says.
The scientists are now working to further elucidate the functions of p300/CBP and to solve larger structures of the protein, with a view to developing inhibitors of p300/CBP activity.