3D Structure of Tumor-Suppressor Protein Generated on the Computer

Researchers at Ohio State University’s 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 molecule’s 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 protein’s 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. Tsai’s 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, we’d 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."