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Mapping the ribosome at the atomic level

October 08, 2009 01:52 pm | Updated November 17, 2021 06:36 am IST - Chennai

Joint winner of the 2009 chemistry Nobel Prize Venkatraman Ramakrishnan, sits in his lab at the Medical Research Council Lab in Cambridge, England on Wednesday.

Joint winner of the 2009 chemistry Nobel Prize Venkatraman Ramakrishnan, sits in his lab at the Medical Research Council Lab in Cambridge, England on Wednesday.

The 2009 Nobel Prize in Chemistry is awarded for the detailed mapping of the ribosome – the cell’s own protein factory. The ribosome translates the passive DNA information into form and function. The ribosome translates genetic information into action.

Ribosomes exist in all cells in all living organisms, from bacteria to human beings. As no living creature can survive without ribosomes, they are the perfect targets for drugs. Many of today’s antibiotics attack the ribosomes of bacteria, but leave those of humans alone. The knowledge that this year’s Nobel Laureates provide us with can thus be of substantial value for the development of new antibiotics. The three Nobel Prize Laureates in chemistry for 2009, Ada E. Yonath, Thomas A. Steitz and Venkatraman Ramakrishnan, are rewarded for mapping the ribosome – one of the cell’s most complex machineries – at the atomic level. The ribosome reads the information in messenger RNA, and based upon that information, it produces protein. Scientists refer to this as translation.

The body contains tens of thousands of different proteins that control what happens in the body with an astounding precision.

The ribosomes

A ribosome is about 25 nanometers (a millionth of a millimeter) in size. A cell contains tens of thousands of ribosomes. Scientists discovered that ribosomes are the locations where proteins are produced. In 1958 they named the protein-producing particle ribosome. It consists of proteins and RNA molecules (ribosomal RNA, or rRNA).

Scientists had identified DNA as the molecule that carries hereditary traits. The sequence of nucleotides controls the sequence of amino acids in proteins, which are produced by ribosomes in the cytoplasm. Yet, DNA and the ribosomes are located on different sides of the nuclear envelope and have no contact with one another.

The answer was provided at the beginning of the 1960s. Scientists realized that the genetic message is copied to a RNA molecule. They called it messenger RNA (mRNA). mRNA moves outside the nucleus and is caught by the ribosome, which uses mRNA as a blueprint for producing proteins.

A complex mechanism is involved by which information flows from DNA to RNA and become enzymes and other proteins. The image was still rather schematic, though. The way a molecule functions cannot be known unless the structure of the molecule is first known.

Hence it became very important to first produce the structure of ribosomes and understand how the atoms are located. It was only in 2000 that the structure that showed how the atoms are located in the ribosome was produced.

The ribosome reads the information in messenger RNA, and based upon that information, it produces protein. This picture is an X-ray crystallographic structure of 30S ribosomal particle from the `Thermus thermophilusâbacterium.

The pioneering and path-breaking effort was first started by Ada Yonath. At the end of the 1970s, she decided to try to generate X-ray crystallographic structures of the ribosome.

The prerequisite for X-ray crystallography is a perfect crystal of a molecule. To obtain high quality crystals from a protein can be a very tough task. And the larger the protein complex, the harder the task.

Exact location

The ribosome is one of the most complicated protein/RNA complexes. It consists of hundreds of thousands of atoms. She wanted to establish the exact location of each and every one of these atoms in the ribosome. Many scientists thought this was very difficult task. And it was indeed one.

She studied the bacteria Geobacillus stearothermophilus can live in warm springs and survives in temperatures up to 75 degree C.

In 1980, she had already managed to generate the first three-dimensional crystals of the ribosome’s large subunit. This was a great achievement, although the crystals were far from perfect. It would actually take another 20 years of hard work before she managed to generate an image of the ribosome where she could determine the location of each atom.

More scientists joined in the race when they realized that the ribosome’s atomic structure could be mapped. Among them were Dr. Steitz and Dr. Ramakrishnan.

At the beginning of the 1990s, Dr. Yonath’s crystals had sufficient quality. The pattern of black dots was detailed enough to determine the location of the atoms in the ribosome crystal. There remained a considerable obstacle, however. It was the “phase problem” of X-ray crystallography.

In order to determine a structure from the pattern of black dots (obtained during the process of X-ray crystallography), scientists needed to know the “phase angle” for each and every dot. This mathematical information is related to the location of the atoms in the crystal.

A trick frequently employed by scientists to determine phase angles is to soak the crystal in heavy atoms, e.g. mercury. The heavy atoms attach to the surface of the crystal’s ribosomes. By comparing the dotted patterns from crystals with and without heavy atoms, scientists can establish the phase angle

However, as the ribosomes are so large, too many heavy atoms attached to the ribosome, and it was difficult to immediately determine the phase angle. Additional information was therefore needed in order to solve the phase problem.

It was Dr. Steitz who finally solved the problem. He used images of the ribosome, generated by Joachim Frank, a specialist in electron microscopy. With the help of those images, Dr. Steitz could find out how the ribosomes were oriented and located within the crystal (but the resolution did not allow him to see individual atoms). This information, together with the information from the heavy atoms, finally yielded the phase angle.

In 1998, Dr. Steitz published the first crystal structure of the ribosome’s large subunit. But it was not possible to see individual atoms, but one could detect the ribosome’s long RNA molecules. This was a decisive breakthrough.

Now that the phase problem had finally been solved, all that remained was to improve the crystals and collect more data, in order to increase the sharpness of the image.

In August and September 2000, they published crystal structures with resolutions that allowed interpretation of the atomic locations. Dr. Steitz managed to obtain the structure of the large subunit from Haloarcula marismortui. Dr. Yonath and Dr. 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.

Molecular ruler

A property of the ribosome, that has fascinated scientists for a long time, is that it seldom makes any errors when it translates DNA/RNA-language into protein language.

If an amino acid is incorrectly incorporated, the protein can entirely lose its function, or perhaps even worse, begin to function differently. For the correct amino acid to be selected depends primarily on the base pairs formed between tRNA and mRNA.

However, this pairing process is not sufficient to explain the ribosome’s precision. Dr. Ramakrishnan’s crystal structures of the ribosome’s small subunit have been crucial for the understanding of how the ribosome achieves its precision. He identified something that could be described as a molecular ruler.

Nucleotides in the small sub-unit’s rRNA measure the distance between the codon in mRNA and the anticodon in tRNA. If the distance is incorrect, the tRNA molecule falls off the ribosome. Using the ruler twice, the ribosome double-checks that everything is correct. This ensures that errors only occur about once per 1,00,000 amino acids.

Search for antibiotics

The Laureates’ work proves useful in the search for new antibiotics.

The ribosome is the target for new antibiotics. Today, humans have an arsenal of different antibiotics which can be used in the fight against disease-generating bacteria. Many of these antibiotics kill bacteria by blocking the functions of their ribosomes.

However, bacteria have become resistant to most of these drugs at an ominous rate. Therefore we need new ones. This year’s three Nobel Laureates in chemistry have all produced structures that show how different antibiotics bind to the ribosome.

Some of them block the tunnel through which the growing proteins leave the ribosome, others prevent the formation of the peptide bond between amino acids. Still others corrupt the translation from DNA/RNA-language into protein language.

Several companies now use the structures of the ribosome in order to develop new antibiotics. Some of these are currently undergoing clinical tests, in order to come to grips with the problem of multiresistant bacteria (e.g. MRSA).

The understanding of the ribosome’s structure and function is of great and immediate use to humanity. The discoveries that the three have made, are important both for the understanding of how life’s core processes function, and in order to save lives.

(Edited excerpts from public information available at www.nobelprize.org)

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