In a landmark achievement, Yale researchers have determined the atomic structure of the ribosome's large subunit, paving the way for more effective drugs to fight infection.
The findings, published in two separate articles in the Aug. 10 issue of the journal Science, were derived in Yale laboratories led by Thomas Steitz, the Eugene Higgins Professor of Molecular Biophysics and Biochemistry and investigator at the Howard Hughes Medical Institute, and Peter Moore, the Eugene Higgins Professor of Chemistry.
"This is like climbing Mt. Everest or running the four-minute mile," Steitz says. "We have solved the structure of the ribosome's large subunit, which is the largest unique structure determined. We have established that the ribosome is a ribozyme, an enzyme in which catalysis is done by RNA, not protein."
The ribosome is the cellular structure responsible for synthesizing protein molecules in all organisms. In addition to enhancing the understanding of protein synthesis, the research offers new clues about evolution and has significant medical implications because the ribosome is a major target for antibiotics.
Many antibiotics cure disease by selectively inhibiting the protein synthesizing activity of large ribosomal subunits in disease-causing bacteria, while leaving human ribosomes alone. Unfortunately, over the years, many bacteria have become resistant to these agents, and the possibility exists that the devastating bacterial diseases that were brought under control by antibiotics in the 1940s and 1950s will once again become scourges.
"Now that we know the structure of the large ribosomal subunit," Steitz says, "we can determine its exact structure with antibiotics bound to it." The same methods of "structure-based drug design" that led to the development of HIV protease inhibitors for AIDS can now be used on the ribosome, which is 100 times larger, he explains.
"The information that emerges should enable pharmaceutical companies to devise new inhibitors of ribosome function that can be used to control bacterial diseases that have become resistant to older antibiotics," Steitz adds.
Although the ribosome is microscopic, it is gigantic in molecular terms. The larger of its two subunits is about 50 times larger than the average enzyme. Its function is to read the genetic information encoded in messenger RNA and generate the protein molecules that the messenger RNA molecules specify. The proteins made by an organism's ribosomes are responsible for virtually all of its properties, including how it looks and behaves.
The structure of the ribosome's large subunit was determined using X-ray crystallography, a technique that can produce three-dimensional images at resolutions so high that individual atoms can be positioned. The 3,000 nucleotides of RNA in the large ribosomal subunit form a compact, complexly folded structure, and its 31 proteins permeate its RNA.
Enzymes composed entirely of protein promote virtually all chemical reactions that occur in living organisms. One of the most remarkable findings to emerge from this research is that the protein synthesis reaction that occurs on the ribosome derives from the two-thirds of its mass that is RNA, not from the one-third that is protein.
"It was suspected for many years that the RNA of the ribosome was the enzymatic component. We now know that for certain," Steitz says. "This means that in the very early days of evolution, protein synthesis evolved using RNA molecules because there were no protein molecules."
Other members of the research team included Yale postdoctoral fellows Nenad Ban, Poul Nissen and Jeffrey Hansen.
-- By Karen Peart
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