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Digging for Genetic Fossils: Hutchinson Center Researchers Solve Structure of Ancient Biological Molecule

SEATTLE — Apr. 12, 2001 — Using an X-ray machine that accelerates particles close to the speed of light, scientists at the Fred Hutchinson Cancer Research Center have gotten a backward glimpse into primordial biology, capturing the dance of a genetic fossil in motion.

Their work, published today in Nature, is the first to capture the structure and choreography of an intricately folded ancient biological molecule as it twists and turns to carry out its enzymatic function.

By solving the 3-D structure of the hairpin ribozyme, found in a virus that infects tobacco plants, lead author Adrian Ferré-D'Amaré, Ph.D., and colleagues discovered that it is strikingly similar in function to the well-characterized ribonuclease A protein, whose structure was determined more than 30 years ago. Although these two enzymes are drastically different from a molecular standpoint, their jobs are the same: snipping RNA — an information-containing molecule similar to DNA — into smaller pieces.

"This was probably the biggest surprise of our study," said Ferré-D'Amaré, an assistant member of the Hutchinson Center's Basic Sciences Division. "Both enzymes have to twist their RNA substrate in the same fashion in order to cleave it. Because the two enzymes are completely distinct, we'd say this is an example of convergent evolution — each independently evolved the same strategy to do the job, probably because there are limited ways to carry out this kind of chemistry."

Ferré-D'Amaré's fascination with RNA stems in part from the theory that it may be the most ancient biological molecule. However, some present-day life forms, such as HIV and poliovirus also use RNA as their genetic material.

"Cells need the ability both to store genetic information and to carry out specific functions through a chain of chemical events called catalysis," he said. "Modern cells use DNA for information storage and proteins for doing the catalytic work, but the primordial cell is thought to have used RNA for both processes. The ribozomes we study today could be considered RNA fossils," said Ferré-D'Amaré, also an affiliate assistant professor of biochemistry at the University of Washington School of Medicine.

Although the study of catalytic RNA is about 20 years old, little is known about how their building blocks are assembled into three-dimensional structures. While thousands of protein structures have been solved, only a handful of RNA structures have been determined.

Molecular structures are solved using a technique called X-ray crystallography, in which X-rays are beamed at molecular crystals, which forms a distinct pattern as the rays are diffracted. Computer programs translate the diffraction pattern to reveal the molecule's three-dimensional properties. In some cases, scientists can determine the resolution of three-dimensional molecular structure to within a millionth of an inch.

For the initial diffraction analysis, the crystal sample was imaged in the Hutchinson Center's X-ray crystallography facility. The researchers then traveled to the University of California at Berkeley, where they completed their diffraction studies using an Advanced Light Source synchrotron at the Lawrence Berkeley National Laboratory.

The Hutchinson Center provides funding for membership in a research consortium that enables investigators to use the Berkeley synchrotron, a machine that accelerates particles close to the speed of light, for structural-biology studies.

A synchrotron provides a more intense diffraction pattern than standard X-ray crystallography, providing much higher resolution of the three-dimensional structure.

The hairpin ribozyme structure uncovered some long-standing questions about how RNAs catalyze reactions, Ferré-D'Amaré said.

"Proteins are assembled from 20 different kinds of building blocks, called amino acids, which give proteins an enormous versatility in their catalytic ability," he said. "In contrast, RNAs are built from only four kinds of building blocks, called nucleotides, meaning that ribozymes must somehow make the most of what they've got."

The team found that the folding of the RNA into its active structure actually changes the chemical properties of its nucleotide building blocks, giving them a much broader range of chemical capabilities needed for catalysis.

"We found that parts of the molecule actually change a lot as they come together to form the active site," said Ferré-D'Amaré, who speculates that improved understanding of RNA activity could lead to the discovery of attractive targets for drug design, particularly in the area of antibiotics.

Editor's Note
To obtain a copy of the Nature paper, please contact the journal at (202) 626-4956.

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Fred Hutchinson Cancer Research Center
Fred Hutchinson Cancer Research Center, home of three Nobel laureates, is an independent, nonprofit research institution dedicated to the development and advancement of biomedical technology to eliminate cancer and other potentially fatal diseases. Recognized internationally for its pioneering work in bone-marrow transplantation, the center's four scientific divisions collaborate to form a unique environment for conducting basic and applied science. Fred Hutchinson, in collaboration with its clinical and research partners, UW Medicine and Children's Hospital and Regional Medical Center, is the only National Cancer Institute-designated comprehensive cancer center in the Pacific Northwest and is one of 40 nationwide. For more information, visit the center's website at