Rebecca Rawls

The best evidence yet that, before there were proteins, there was once a world in which RNA both provided genetic information and catalyzed chemical reactions comes from a trio of papers in the current issue ofScience. In a tour de force of X-ray crystallography, chemists at Yale University have located most of the atoms in the gigantic apparatus that cells use to link amino acids together into proteins. The heart of the apparatus where peptide bonds form, they find, is composed entirely of RNA.

Yale team includes, from left, postdoc Nenad Ban, Steltz, Moore, and postdoc Poul Nissen. Not shown is postdoc Jeffrey Hansen.

The Yale chemists have resolved the structure of the large subunit of the ribosome [Science, 289, 905, 920, and 947 (2000)]. Ribosomes in cells from all classes of organisms have so many common features that biologists believe the structure itself has been preserved essentially unchanged since the very earliest days of life's history.

The Yale structure answers the "chicken and egg" problem of protein synthesis, says Thomas A. Steitz, who, along with Peter B. Moore, led the X-ray crystallography effort. Steitz and Moore are both professors of chemistry, biochemistry, and molecular biophysics at Yale. Steitz is additionally a Howard Hughes Medical Institute investigator. "In the beginning," Steitz says, "before there were proteins, how could you have a protein-catalyzed synthesis of a protein?" Since the 1960s, an increasing number of researchers have been arguing that the first biocatalysts were RNAs, and that they catalyzed the synthesis of the first proteins.

Space- filling model represents large subunit of the ribosome looking down the cleft into the active site, identified by the presence of red inhibitor molecule. RNA's sugar-phosphate backbone is shown in orange; its bases are white. Proteins, shown in blue, surround the perimeter of the complex but are not present at the active site. The structures of two proteins, labeled L1 and L11, are known only at lower resolution; only their backbones are shown in this model. Adapted from Science

"There are no proteins in the neighborhood of the site on this particle where catalysis occurs and covalent bond formation takes place," Moore points out. "So that activity of the ribosome is RNA-driven." Although there has been lots of earlier evidence suggesting this might be true, "it's nice to have it finally, cleanly settled. And it is settled," Moore says.

The work is "very exciting," says Carl R. Woese, professor of microbiology at the University of Illinois, Urbana-Champaign and an early advocate of RNA-catalyzed protein synthesis. "Whenever false ideas are completely demolished, it's a good thing, and that's what this structure is doing."

The structure shows that this subunit of the ribosome functions as a catalyst in two ways. It orients the two substrates, as protein enzymes do, although in this case the orientation occurs because of RNA-RNA interactions between the ribosome and the RNA molecules transporting amino acids to the site of synthesis. Additionally, the subunit contains a base whose chemical properties are modified by the environment in which it sits, so it functions as a general acid-base catalyst. In one paper of the series, Scott A. Strobel and his colleagues explore this aspect of the catalysis in detail. Strobel is associate professor of chemistry, biochemistry, and molecular biophysics at Yale.

RNA is particularly well-suited to recognize and interact with other RNA molecules, as happens in protein synthesis, suggests chemistry Nobel Laureate Thomas R. Cech in a perspective that accompanies what he calls "these landmark publications."

The structure is likely to do more than settle one issue in evolutionary biology. Atomic resolution structures of RNA are still relatively rare, so that this one structure, which is about two-thirds RNA and one-third protein, increases by a factor of four or five the amount of structural data available on RNA. It includes 2,833 of the subunit's 3,045 nucleotides and 27 of its 31 proteins.

"From the point of view of someone interested in general properties of RNA folding, we have just provided an encyclopedia," Moore says. He expects the structure to also have an important impact on people's understanding of how proteins interact with RNA.

"Just seeing the architecture of how this whole thing is put together is neat!" Steitz says. "I think it's going to be an incredible database for understanding how RNA folds. Everybody--including ourselves--will look at this RNA structure and ask: What are the principles of folding in RNA? And can we use these principles to predict the structure of other RNA?"

At least one atomic resolution structure of the other subunit of the ribosome is expected shortly. Venki Ramakrishnan, an investigator at the Medical Research Council Laboratory, Cambridge, England, says he has two papers on this structure in press, including views of the subunit complexed with three different antibiotics. Both the Yale and Cambridge groups published lower resolution structures of their respective subunits last year (C&EN, Aug. 30, 1999, page 14).

Like Ramakrishnan, the Yale group is also investigating the interactions of their subunit with various antibiotics. "We are going to be able to get involved in structure-based drug design with our structure at quite a respectable level, I believe," Steitz says. The ribosome is one of the most important targets of existing antibiotics, he notes, which makes it of prime interest for future drug design. Although their plans are still in flux, Steitz anticipates that the Yale group will start a small biotechnology company in New Haven that will work with various pharmaceutical houses on structure-based drug design.

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