3-D Structure of Human Tumor-Suppressor Protein Produced

March 02, 1998

COLUMBUS, Ohio -- Researchers here have determined the three-dimensional structure of the protein produced by one of the most important human tumor-suppressor genes.

The gene is the p16 tumor-suppressor gene. The protein produced by this gene, the p16 protein, normally prevents cells from dividing when they shouldn’t.

When this protein is missing or inactivated due to mutations in the p16 tumor-suppressor gene, cancer can occur. In fact, damage to the p16 protein is a factor in more than 70 different types of cancer.

The researchers have also produced computer-generated pictures of the protein.

“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, the researcher at Ohio State University’s Comprehensive Cancer Center who led the study.

“If we can develop a drug that mimics p16, that would be a potentially good approach for the treatment of cancer, which is the ultimate goal of work like this.

“Determining the structure of the protein is the first major step in developing such a drug,” said Tsai, a professor of chemistry and of biochemistry.

The study, conducted by Tsai and a team of Ohio State researchers, was published in a February issue of the journal Molecular Cell. They 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.

NMR spectroscopy uses a powerful magnetic field to make molecular measurements. The method enables the researchers to study the structure of the p16 protein in a water solution, which more closely represents the molecule’s 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.

Tsai’s study took three years to complete because the p16 protein is unusually flexible compared to many other protein molecules.

“Because of this flexibility,” said 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 research on the p16 protein.

“We now know the structure of the p16 protein alone,” said 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.”

This project was supported by grants from the National Cancer Institute and the American Cancer Society.
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Written by Darrell E. Ward, (614) 292-8456; Ward.25@osu.eduEDITOR’S NOTE: A computer-generated image of the p16 protein in black and white and in color are available in jpeg format. The illustrations display a “ball-and-stick” model showing the placement of atoms in the p16 molecule. To obtain a copy of the images contact Darrell Ward at (614) 292-8456 or at: ward.25@osu.edu
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Ohio State University

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