Researchers at Ohio State Universitys Comprehensive Cancer
Center have determined the three-dimensional (3D) structure of the
protein produced by the p16 tumor-suppressor gene. This protein
normally prevents cells from dividing inappropriately. When the p16
protein is missing or inactivated because of mutations in the p16
gene, cancer can occur. In fact, damage to the p16 protein is a
factor in more than 70 different types of cancer.
Ultimate Goal of the Research
The researchers have generated computer pictures of the protein (Figure
1). "This was a major achievement because of the importance
of this protein in cancer and because of the difficulty of the
project," said Ming-Daw Tsai, PhD, professor of chemistry and biochemistry.
"If we can develop a drug that mimics p16, that could
potentially be a good treatment approach for cancer, which is the
ultimate goal of our research," said Dr. Tsai. "Determining
the structure of the protein is the first major step in developing
such a drug," he added.
The study was published in a February issue of Molecular Cell.
Researchers used nuclear magnetic resonance (NMR) spectroscopy to
measure the location of the atoms within the protein and their
distances from one another. This information was then fed into a
computer to determine the molecules structure.
By using NMR spectroscopy, researchers were able to study the
structure of the p16 protein in a water solution, which more closely
represents its structure as it would exist inside the cell. This, in
turn, will make it easier, through further research, to determine the
proteins active sites--locations on the p16 molecule that
interact with other molecules in the cell to suppress cell division.
Accurate knowledge of the active sites is essential for developing a
drug that can duplicate the tumor-suppressor action of the molecule.
Interaction Between p16 Protein and Cellular Target Molecule to Be Studied
Dr. Tsais study took 3 years to complete because the p16
protein is unusually flexible compared to many other protein
molecules. "Because of this flexibility," said Dr. Tsai,
"the molecule was in constant motion, making it difficult to
make the measurements we needed to establish the structure."
Tsai and his research team are continuing their study of the p16
protein. "We now know the structure of the p16 protein
alone," said Dr. Tsai. "Next, wed like to know how
p16 interacts with its target molecule in the cell." That target
is a second protein--cyclin-dependent kinase 4 (cdk4). "If we
can determine the structure of the two proteins together," he
said, "it will be the next major step toward designing drugs
that block the inappropriate cell division that leads to cancer."