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HUTCH IN THE NEWS HEADLINE NEWS SCIENCE SPOTLIGHT OFF THE TOP NEWS & FEATURES HR NEWS COLUMNS UPDATES |
A 'longer chain of
reasoning' By Dr. Barbara Berg
folded RNA molecules carry out enzymatic functions previously thought to be the sole domain of proteins. While crystallography has been a powerful tool for deciphering the structure of proteins, RNA molecules have stubbornly resisted forming orderly crystals, the critical step in this technique's success. Ferré-D'Amaré overcame this obstacle by developing a method for tricking RNA molecules into forming crystals, enabling him to determine the three-dimensional structure of a ribozyme encoded by the hepatitis delta virus. His work, published in the journal Nature in November 1998, gives researchers the first hint that at least some ribozymes have structures that look a lot like protein enzymes. "The promise of Adrian's work is that he's on the leading edge of studying how RNA molecules can fold and function in biology on their own," says Dr. Roland Strong, also of Basic Sciences. "Where there's literally thousands of protein structures known, there's only a handful of RNA structures known." Fluent in four languages, Ferré-D'Amaré has a cultural background as diverse as the structures he investigates. His mother, a Japanese violin soloist, and father, an archaeologist of Catalonian descent, moved frequently when Ferré-D'Amaré was a child. He has lived in Japan, Austria, Prague, Chicago and Mexico. Ferré-D'Amaré acknowledges that his early interest in science may have been sparked at least in part by his father's work. "I grew up in a scientific culture," says Ferré-D'Amaré. "I got to go on digs," he remembers, noting that "kids love dirt." All that digging may have prompted an early fascination with field work, particularly in the area of marine biology. "I bought books on classification of mollusks and coral reef ecology," he says. "I was very interested in marine biology for about 10 years and spent time working at marine research stations in Japan and Mexico." Ferré-D'Amaré began his undergraduate studies in Mexico as a marine biology major, eventually switching to chemistry a few years later after becoming frustrated with some of the limitations of field biology.
work in the laboratory of Dr. Stephen Burley, an x-ray crystallographer who studies the structure of DNA-binding proteins. Ferré-D'Amaré's graduate research focused on the structure of a class of DNA binding proteins known as HLH (helix-loop-helix) proteins, leading to his elucidation of the structure of the Max protein bound to DNA. Max, discovered in 1991 by Basic Sciences investigator Dr. Bob Eisenman, interacts with the myc protein, which is implicated in cell proliferation. "A key question with Max at that time was how it selectively interacts with myc but not with other members of the HLH family," Ferré-D'Amaré says. "Scientists need a three-dimensional template to really interpret the results of other experiments." In 1994, when Ferré-D'Amaré was completing his graduate studies, Dr. Jennifer Doudna interviewed for a position at Rockefeller and gave a seminar on her attempts to determine the crystal structure of a ribozyme. Ferré-D'Amaré was immediately intrigued. "RNA structure is really interesting," he says. "Besides proteins, RNA is the only other thing in the cell that folds up." Doudna eventually accepted a faculty position at Yale, and Ferré-D'Amaré decided to do his postdoctoral work in her lab. "I joined her lab before it even existed," he says. "When she finally set up her lab, I moved to New Haven." Ferré-D'Amaré decided to focus on the ribozyme encoded by the hepatitis delta virus (HDV) a satellite virus of the more commonly known hepatitis B virus because it is a very stable enzyme, making it more likely that it would be less refractory to work with than other RNA molecules. The function of this ribozyme, the only known to be required for a human pathogen, is to cleave itself into smaller fragments of RNA. "I thought it would be easy to crystallize, but I was wrong!" says Ferré-D'Amaré. He spent the first two years in Doudna's lab devising a method to coax the RNA into arranging itself into crystals. Proteins form crystals much more readily than RNA, mainly because proteins have a much greater variety of exposed groups on their surface. To facilitate crystallization, Ferré-D'Amaré engineered the ribozyme to contain a small portion of a protein molecule. This small protein patch doesn't affect the function of the ribozyme, allowing it to still retain its catalytic activity. Once Ferré-D'Amaré obtained crystals, his work proceeded smoothly, enabling him to solve the structure of the hepatitis delta ribozyme. The structure reveals that the enzyme has a very complicated fold, very similar to that found in the active sites of proteins, and may have implications for future drug design using the ribozyme as a target. Since joining the Center in September, Ferré-D'Amaré has focused his efforts on determing the structures of other catalytic RNAs as well as on learning the details of their mechanisms of catalysis. "I'd like to keep the lab size really small so that I can stay in touch with what's going on. We'll keep a fairly focused approach." Ferré-D'Amaré is pleased by the Center's "great environment. It's really open and friendly with a lot of communication." He and his structural biology colleagues look forward to a lot of interaction through joint lab meetings and shared facilities. "We are delighted to have Adrian here," says Basic Sciences investigator Dr. Barry Stoddard. "He brings great expertise in a variety of areas that complement our existing research, particularly in the area of RNA mechanism and structure." |
