Ada Yonat's work made it possible to decipher and understand the mechanism of action of five antibiotic drugs

The Weizmann Institute of Science congratulates Prof. Ada Yonat on winning the Nobel Prize in Chemistry for 2009, and is proud of her scientific achievements.

The following message was received from the Weizmann Institute Prof. Ada Yonat winning the 2009 Nobel Prize in Chemistry.

We are happy that the Nobel Prize Committee recognized the importance of Prof. Yonat's scientific work, and awarded her this important prize.

Prof. Yonat's research was motivated by curiosity and a desire to better understand the world and our place in it. This research aimed towards a high goal: understanding one of the most complex "machines" in biological systems.

At the end of the XNUMXs, Prof. Yonat, who was then a young scientist at the Weizmann Institute of Science, decided to challenge one of the key questions regarding the working methods of living cells: to decipher the structure and principles of operation of the ribosome, the cell's protein factory. This was the beginning of a long journey that lasted decades, and required originality, courage and adherence to the goal. This is a research journey that began in a modest laboratory with a modest budget, and over the years expanded to include dozens of researchers under the leadership of Prof. Yonat.

This basic research, which began with an attempt to understand one of the principles of nature, led, later, to the understanding of the way in which several antibiotic drugs work, which may help in the development of more advanced and effective antibiotic drugs. This discovery may help in the fight against bacteria that have developed resistance to antibiotics, a problem defined as one of the main medical challenges of the 21st century.

Prof. Yonat is an example of the way in which a scientific vision, courage in choosing a great scientific question, and adherence to the goal - may lead to success and the expansion of human knowledge, for the benefit of all human beings wherever they are.

An explanation of Yonat's work

The award was given to Prof. Yonat for deciphering the structure and understanding the principles of operation of the ribosome, the protein factory of the cell, the achievement, which was made possible thanks to the development of an original research method, may help, among other things, in improving the effectiveness of antibiotic drugs and possibly also in curbing the uncontrolled production processes of proteins that cause various diseases , including cancer

Weizmann Institute scientists were able to map the electron density in the small subunit of the ribosome, an intracellular organelle that serves as the "body's protein factory". Proteins are the main substances that carry out life processes and their activity depends on both their chemical composition and their spatial structure. The ribosome, which produces the proteins according to the information contained in the genes, itself consists of a large number of proteins and nucleic acids organized into two subunits. The process of the formation of the proteins in the ribosome is one of the most basic and intriguing life processes. Deciphering this mystery may help, among other things, in improving the effectiveness of antibiotic drugs and possibly also in curbing the uncontrolled production processes of proteins that cause various diseases, including cancer.

Many scientists in different parts of the world have been trying for several decades to decipher and understand the structure of the ribosome and its mode of activity. The current achievement of the scientists of the Weizmann Institute, achieved in collaboration with the scientists of the Max Planck Institute in Germany, advances this long research journey towards achieving its goal. To discover the spatial structure of biological molecules and other microscopic structures, scientists create crystals from them. They irradiate these crystals with X-rays (x-rays). Measuring the radiation scattered from the crystal may teach about the spatial structure of the molecules that make it up. This technology is called X-ray crystallography. One of the outstanding difficulties in this field is obtaining information about the structure of the studied unit, at a sufficient level of separation (resolution) between point to point in the "electron map" of the studied molecule. This "map" is obtained as a result of calculating the X-ray scattering data from the crystal. But, the ribosome is a very complex structure, unstable and lacking internal symmetry, properties that make it very difficult to create crystals from it, or from its subunits. In fact, despite the fact
Prof. Yonat was able to grow ribosome crystals that scatter radiation to a resolution of three angstroms, so far the researchers have not been able to obtain information about the components of the ribosome at a resolution that exceeds five angstroms. (An angstrom is one hundred millionth of a centimeter).

Prof. Ada Yonat from the Department of Structural Biology at the Weizmann Institute of Science and from the Ribosome Research Unit at the Max Planck Institute in Germany, recently broke through this barrier, thanks to new techniques of crystallography, the result of her development. This is how she managed to obtain an "electron density map" of the small subunit of the ribosome (called S 30) with a resolution of 4.5 angstroms. This unit is responsible for "translating" the genetic code carried in the messenger RNA molecules, into the information according to which the ribosome produces proteins. These findings are published today, December 7, 1999, in the journal "Records of the American Academy of Sciences" (PNAS).

Prof. Yonat: "In order to decipher the spatial structures of biological materials, it is necessary to create and study crystals composed of derivatives of these materials, as well as crystals composed of the (whole) natural materials. But, in attempts to decipher the secret of its structure and methods of operation

The ribosome It turned out that crystals made from derivatives of the ribosome have a lower dispersibility than the ribosome itself, which made it difficult to map and describe the structure of the ribosome. Another obstacle that made it difficult to cross the five angstrom barrier stems from the fact that in order to get a better resolution, the crystal must be irradiated with X-rays of increased intensity, which destroys the crystal. Successful crystallographic mapping depends both on the ability to create a fine balance between the radiation intensity and the amount of information obtained on the crystal structure, and on the ability to create improved derivatives. For this purpose, we integrated in selected sites of the ribosome, markers that are, in fact, heavy atoms, which stand out in the electron density map because they contain many electrons. These markers allowed us to significantly improve the quality of the mapping of subunits of the ribosome."

Later, Prof. Yonat and the members of the research group she heads were able to "photograph" the S 30 subunit during activity, at the stage when the first contact is made between the messenger RNA molecule and the ribosome. This contact signals the possibility of starting the production process of a protein according to the genetic information. To do this, Yonat and her colleagues had to activate the ribosome inside the crystal, despite the limitation of movement that characterizes the crystalline state. After that, the messenger RNA molecule, which was designed to stick tightly to the ribosome, was inserted into the crystal. The activation method of ribosomes was previously developed at the Weizmann Institute of Science, by professors Ada Zamir, Ruth Miskin and David Elson.

In previous studies, Prof. Yonat managed to create the first ribosome crystals in the world, and she is also the first to identify actual evidence of the existence of a "tunnel" inside the active ribosome, which is used to protect newly formed proteins, until they form into a structure that allows them to "protect themselves". Prof. Yonat developed several techniques that are currently common in the field of structural biology in the world. The most well-known and widely used technique is called cryo-crystallography, that is, exposing the crystal to a low temperature - minus 185 degrees Celsius, which prevents the

The disintegration of the crystal as a result of irradiation with strong X-rays. In addition to this, it has developed unique experimental systems for researching the ribosome, such as this one based on the use of ribosomes taken from bacteria that exist in the Dead Sea. These research methods are currently used by many researchers in many parts of the world.

Prof. Yonat: "The new progress we achieved in the long journey to decipher the structure and mode of action of the ribosome, may pave the way, in the future, to improve the effectiveness of various antibiotic drugs, aimed at inhibiting the ribosomal activity of disease-causing bacteria. The same understanding could perhaps, in the future, help us curb the uncontrolled production processes of proteins that cause various diseases, including cancer."

This work made it possible to decipher and understand the mechanism of action of five antibiotic drugs

Five antibiotic drugs succeed in paralyzing the normal functioning of bacteria, thanks to the fact that they stick to the ribosomes that are found and work in these bacteria. As a result of the adhesion, the ribosomes that are the "protein factories of the cell" are paralyzed, which disrupts the bacteria's protein production. The proteins are the main biochemical components that activate the various life activities, and a disruption in their production processes causes the bacteria to die.

The team of researchers working at both institutes, led by Prof. Ada Yonat from the Department of Structural Biology at the Weizmann Institute of Science, recently discovered how, exactly, these drugs work. Prof. Yonat recently revealed the complex structure of the ribosome. This research work, which lasted about twenty years, was crowned by the prestigious scientific journal "Science" as one of the most important research works of the year 2000. Based on the knowledge of the structure of the ribosome, Prof. Yonat, Dr. Anat Bashan and research student Raz Zaribetz from the Weizmann Institute decided to science, to try and find out how different antibiotic drugs bind to the ribosome and paralyze it. To do this, they prepared crystals of certain structural units of ribosomes from bacteria that were each treated with one of five known antibiotic drugs.

At this stage, the scientists deciphered the spatial structure of the ribosome units that make up the crystals, by bombarding the crystals with X-rays ("x-ray") and monitoring the dispersion of the radiation that hit the crystal (a technology called X-ray crystallography). With this method, the scientists were able to distinguish the molecules of the antibiotic drugs when they are adjacent to the activity sites of the ribosome in a way that thwarts its normal operation. The findings of this research are published today in the prestigious scientific journal "Nature".