Snapshot of new drug marks a major advance by Memorial Sloan-Kettering researchers

are wrapped. For a gene in a DNA chain to be turned on, or "expressed," the DNA chain must be unwrapped from the histone core. Histone deacetylase keeps the DNA and histones tightly wrapped. So when SAHA inhibits histone deacetylase, it allows the DNA to unwrap, making genes accessible to the cellular switches that turn them on.

The pictures in the recent Nature paper were produced in the laboratory of structural biologist Dr. Nikola P. Pavletich by postdoctoral investigator Dr. Michael S. Finnin. Using the technique of x-ray crystallography, they show the critical parts of the structure of SAHA, trichostatin A, and an analogue of human histone deacetylase (a lookalike counterpart enzyme from bacteria). The pictures also show precisely how both SAHA and trichostatin A hinder the enzyme's activity.

The enzyme has a narrow, deep pocket, at the bottom of which is the active site - the atoms where SAHA and trichostatin A bind. The critical parts of SAHA and trichostatin A are the binding end, which is made up of a substance called hydroxamic acid, and a long narrow chain of atoms that allows the hydroxamic acid to reach all the way to the bottom of the pocket. The combination produces a snug fit, like a lock and key.

"Now that we know what these inhibitors look like, and how they fit and work, we already have ideas about how to improve them, and can do this faster," Dr. Pavletich said. For example, the SAHA molecule could be modified to make its long chain fit better in the enzyme's pocket, or to make the drug dissolve more readily so that it will stay longer in the blood. "This demonstrates the power of structural biology," Dr. Pavletich said. "If you can see the structure, that can be extremely powerful in the development of a drug."

Dr. Finnin noted that histone deacetylase normally interacts with a very large complex of proteins that may regulate it. Each part of the complex may perform a specific task to help the enzyme work. "The next

Contact: Christine Westerman
Memorial Sloan-Kettering Cancer Center

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