By Robert F. Service
ScienceNOW Daily News
7 October 2009

Just as architects usually get more glory than carpenters, DNA is more famous than the molecular machine that converts genetic blueprints into proteins. But the ribosome is in the limelight today with the announcement of this year’s Nobel Prize in chemistry.

The prize was awarded to three scientists who revealed the atomic structure and inner workings of the ribosome: Ada Yonath of the Weizmann Institute of Science in Rehovot, Israel; Thomas Steitz of Yale University; and Venkatraman Ramakrishnan of the Medical Research Council Laboratory of Molecular Biology in Cambridge, United Kingdom. All three used a technique known as x-ray crystallography to pinpoint the position of thousands of atoms in the cellular machine known as the ribosome, and all will share one-third of the $1.4 million prize.

“It’s a fantastic accomplishment and one that everyone in the field has known for some time is worthy of such recognition,” says Wayne Hendrickson, an x-ray crystallographer at Columbia University. Hendrickson adds that this year’s prize also completes the Nobel Committee’s recognition for the discoverers of biology’s central dogma, which describes how genetic information in DNA is copied into RNA, which is then translated into proteins. In 1962, James Watson, Francis Crick, and Maurice Wilkins were awarded the Nobel for their atomic model of DNA. In 2006, Roger Kornberg won for his x-ray structures of RNA polymerase, which translates DNA into RNA. Today’s prize for work on the ribosome completes that, Hendrickson says.

Ribosomes exist in all cells in all living organisms. Although central, they are anything but simple. Dozens of different proteins and strands of RNA form a complicated machine divided into two principal components. The smaller component, known as the 30S subunit, works mainly to decode the genetic code in messenger RNA. The larger 50S subunit then takes this information and uses it to stitch together the proper sequence of amino acids that make up the final protein. Early on, researchers struggled to map the atomic structure of even one of these subunits. Producing an x-ray structure requires first creating crystals of millions of copies of a ribosome aligned in near perfect order. If that ordering is precise enough, researchers can then fire a beam of x-rays at the crystal. The pattern in which those x-rays then deflect off the crystal can then be used to map out the arrangement of atoms in the molecule.

In 1980, Yonath managed to generate the first low-quality crystals of a ribosome. By 1990, she had upped the quality of her crystals, but she still struggled to a good structure. Steitz, along with his longtime Yale colleague Peter Moore, jumped into the fray in 1995, following Yonath’s recipe for making ribosomal crystals. By 1998, they used additional insights gleaned from electron microscopy studies to help them acquire a low-resolution 9 Angstrom structure of the ribosome. In August, 2000 Steitz’s group then published a higher 2.4 Angstrom resolution structure of the large subunit (Science, 11 August 2000, p. 905). Meanwhile, Yonath’s and Ramakrishnan’s groups published slightly lower resolution structures of the smaller subunit the following month. Since then, the three groups, plus other teams, have used those structures and others to understand in atomic detail how ribosomes translate genetic information into proteins.

The three groups have also begun to push practical applications of their work. All three, for example, have reported crystal structures that show how different antibiotics bind to the ribosome. And several companies are now using these structures in an effort to design new antibiotics against worrisome infections, such as methicillin-resistant Staphylococcus aureus and tuberculosis.

But Steitz, for one, says he never thought initially that anything more than a fundamental insight into the molecular workings of biology would come of the work. “It seemed a bit like trying to climb Mount Everest,” Steitz says. “We knew it was doable. But we didn’t know how to get there. When we got there in 2000, it was exhilarating. In fact, it was the most exhilarating moment I’ve had in science.”

• Correction:

The original version of the story stated that Roger Kornberg won a 2006 Nobel Prize for his work on DNA polymerase, which translates DNA into RNA. That translation is carried out by RNA polymerase. Kornberg was awarded his Nobel prize for his crystallography work on RNA polymerase. Thanks to several readers for pointing out our error.

Ribosome Structure Chemistry Nobel Prize 2009

Ribosomal Crystalline Structure Analysis Explains Protein Activities

The crystalline structure of ribosomes has been studied by three scientific groups and the group leaders have received the 2009 Nobel Prize for explaining ribosomes.

In scientific inquiries, some questions are answered quickly, other inquiries may take decades or more. The X-ray crystallography of DNA by Watson, Crick, and Wilkins only took a few years. The work described here for ribosome structure took almost three decades – it was worth the investment. Drs. Ramakrishnan, Steitz and Yonath made major contributions to ribosome crystallography and used high-resolution functional ribosome complexes to unravel mysteries of protein synthesis. Basic science and medicine benefit immensely from these findings. Read the story that revealed details of ribosome structure.

The Nobel Laureates for Chemistry 2009.

These 3 senior scientists and lab directors each shared the chemistry prize for 2009:

• Venkatraman Ramakrishnan. US citizen, Senior Scientist and Group Leader at Structural Studies Division, MRC Laboratory of Molecular Biology, Cambridge, UK.
• Thomas A. Steitz, US citizen. Sterling Professor of Molecular Biophysics and Biochemistry and Howard Hughes Medical Institute Investigator, Yale University, CT, USA.
• Ada E. Yonath, Israeli citizen. Director of Helen & Milton A. Kimmelman Center for Biomolecular Structure & Assembly, at Weizmann Institute of Science, Rehovot, Israel

The Nature, Structure and Function of Ribosomes, Early Crystallography.

The ribosome’s overall basic, simple structure and functions are well-known. There are 70S ribosomes common to prokaryotes and mitochondria and chloroplasts, and 80S ribosomes common to eukaryotes. Ribosomes assist exclusively in protein synthesis.

large subunit, and 20 years later Yonath generated ribosome images to determine each atom’s location. Yonath stabilized crystals by freezing them (liquid nitrogen at -196 °C) and she crystallized ribosomes from other resilient micro-organisms.Yonath’s X-ray crystallography yielded a 3-D ribosome picture of the very stable ribosomes from Geobacillus stearothermophilus, a hot-spring inhabitant, able to survive temperatures up to 75 C. Later Yonath studied ribosomes from the salt-loving Haloarcula marismortui from the Dead Sea. These ribosomes also are very stable, form good crystals and helped locate each atom in the X-ray crystal. Eventually, it was realized that the ribosome’s atomic structure could be mapped, and more scientists joined in the race to determine this – especially, Thomas Steitz and Venkatraman Ramakrishnan.

Molecular Insights into Ribosomes X-Ray Diffraction Studies of Protein/RNA Complexes

Every ribosome has two subunits, 1 small and 1 large. In humans, the small, ribosome unit has 1 large RNA mol­ecule and about 32 proteins; the large subunit has 3 RNA molecules, and about 46 proteins. Each subunit has thousands of nucleotides and amino acids, with hundreds of thousands of atoms. In ribosomal, X-ray diffraction there are millions of atoms to see and study.

In the early 1990s, Yonath’s crystals had clear patterns of black dots, helpful for determining atomic locations, but lacking necessary phase angles for each atom in the X-ray crystal­lography. Soaking the crystal in mercury, tagged the ribosome’s surface and permitted comparisons of the crystalline dotted patterns, with and without heavy atoms. Because ribosomes are so large, too many heavy atoms attached to the ribosome, and it was difficult to immediately determine the phase angles.

Steitz used ribosome images, prepared by the electron microscopist, Joachim Frank, to determine phase angles. Using information from heavy atoms, the phase angle was determined. In 1998, after about 20 years of work, Steitz published the first crystal structure of the ribosome’s large subunit with a resolution of 9 Ångström (1 Ångström = diameter of a hydrogen atom). Individual atoms were not visible, but long RNA molecules were revealed when the phase problem was solved, and improved crystals and more data, clarified the ribosomal image.

These 2009 Nobel Chemistry Laureates each published, in the year 2000, the final crystalline ribosomal structures with resolutions that allowed interpretation of atomic locations. Steitz imaged the large ribosomal subunit of Haloarcula marismortui. Yonath and Ramakrishnan obtained the structure of the small subunit from Thermus thermophilus. Thus, it was possible to map ribosome function­ality at the most basic, atomic level.

Sources

Lodish, H. et al. 2000. Molecular Cell Biology. Fourth Ed., W. H. Freeman and Co., New York, N.Y.

Nobelprize.org. 2009. Chemistry Award for 2009.

Ribosome Crystal with tRNA in Grooves

DNA Transcription and RNA Translation

Ada Yonath, Nobel Prize 2009 Chemistry, Israel

Ramakrishnan team Nobel Prize Day, R far L

Thomas A. Steitz,Yale, 2009 Chemistry Nobel