Nobel Ribosomes
Nobel Prize in Chemistry – 2009 Peter Petrov, Elements
This year, as in the past, biologists will be awarded the Nobel Prize in Chemistry again: their achievements are primarily related to the use of X-ray diffraction analysis, widely used in biochemistry and brought to a new level with the active participation of laureates.
The award will be shared by three biochemists: Ada E. Yonath from the Israeli Weizmann Institute of Science, Venkatraman (Venki) Ramakrishnan, a US citizen currently working at the Cambridge Laboratory of Molecular Biology of the Medical Research Council (Medical Research Council Laboratory of Molecular Biology), and Thomas A. Steitz of Yale University.
The prize was awarded to them "for studies of the structure and function of the ribosome" ("for studies of the structure and function of the ribosome"). Ribosomes, in the study of the structure and mechanism of which the laureates of this award played a key role, are an integral component of all living cells. With their help, all proteins are synthesized on the information RNA matrix in cells, including enzymes that control all chemical processes occurring in the cell.
Ada Yonat was born in 1939 in Jerusalem to a very poor Jewish immigrant family. She received a bachelor's degree in chemistry in 1962 and a master's degree in biochemistry in 1964 from the Hebrew University in Jerusalem. A significant part of her later scientific career was associated with the Weizmann Institute in Rehovot, where in 1968 she received her doctorate for X-ray diffraction studies. In 1969-70, she worked in the United States, including at the Massachusetts Institute of Technology. Since 1988, she has been working as a professor at the Department of Structural Biology at the Weizmann Institute, and since 1989 she has headed a research center at this institute studying complexes of biological molecules. In parallel with her work at the Weizmann Institute, Ada Yonat lectured and led research at several other scientific institutions in Israel, Germany and the USA.
Venki Ramakrishnan was born in 1952 in the town of Chidambaram in southern India, in a family belonging to the Brahmin caste. His childhood was spent in another Indian city, Baroda (now called Vadodara), where he subsequently studied at the university and in 1971 received a bachelor's degree in physics, after which he left for the United States, where in 1976 he received a doctorate, also in physics, at Ohio University. After that, he decided to leave physics and take up biology. He studied biology at the University of California, San Diego for two years, then worked at Yale University (where his ribosome research began) and at several other scientific institutions in the United States, and in 1999 moved to England, where he headed a research group at the Laboratory of Molecular Biology in Cambridge. Since 2008, he has also been a fellow of Trinity College, Cambridge University.
Thomas Staitz was born in 1940 in Milwaukee (Wisconsin). He received a bachelor's degree in chemistry from Lawrence University in Wisconsin, and then studied at Harvard, where he received a doctorate in biochemistry and molecular biology in 1966. From 1967 to 1970 he worked at the Laboratory of Molecular Biology of the Medical Research Council in Cambridge, and since 1970 he has been working at Yale University, where he is currently a professor of molecular biophysics and biochemistry. In addition to Yale, Staitz is also an employee of the Howard Hughes Medical Institute. Thomas Staitz's wife, Joan Staitz, is also a professor of molecular biophysics and biochemistry at Yale.
Although the wording "for studies of the structure and work of ribosomes" is rather vague, apparently, this prize was awarded for quite specific achievements – the first models of the structure of ribosomes at the atomic level obtained using X-ray diffraction analysis.
Ribosomes are protein factories that work in all living cells. The ribosomes of prokaryotes are smaller in size than the ribosomes of eukaryotic cells, but both consist of two subunits, large and small, each of which is built from several RNA molecules (this is the so-called ribosomal RNA, or rRNA) and several dozen different proteins. The mechanism of ribosomes has been studied for decades, but many details of this mechanism still could not be found out, and detailed models of the structure of ribosomes were obtained only at the turn of the XX-th and XXI centuries.
Methods of X-ray diffraction analysis allow us to judge the structure of biological macromolecules and their complexes (in particular, these methods helped to establish the structure of DNA in 1953). X-ray diffraction analysis is based on obtaining crystals of macromolecules and X-ray transmission of them. By the nature of the diffraction of X-rays passing through these crystals, it is possible to judge the structure of the molecules forming crystals. However, by the beginning of the eighties of the XX century, no one had yet managed to obtain crystals suitable for analysis of either complete ribosomes or their individual subunits.
The first successful attempts to crystallize ribosomes to study their structure using X-rays were made in the eighties by Ada Yonat in Berlin and, independently of her, by a group from the Protein Institute in Pushchino, which included Marat and Gulnara Yusupov, who subsequently continued ribosome research in the West. But a serious breakthrough in this direction was made only in the early nineties, when Ada Yonat's group demonstrated the possibility of obtaining crystals of a large subunit of the prokaryotic ribosome, giving a diffraction pattern with a resolution that allows determining the position of individual atoms (up to 3 A and less; at the same time, the size of the ribosome is about 200 A). But the first plausible models of the ribosome structure were obtained only after the crystallization technology and the method of analyzing X-ray structural data were improved during joint research by the group of Peter Moore and Thomas Staitz at Yale University. In 2000, a joint paper of these groups was published in the journal Science, in which the structure of a large subunit of the bacterial ribosome was described in detail (with atomic resolution) for the first time.
Large subunit models with increasing resolution: 9 angstroms (left), 5 (center) and 2.4 (right).
An illustration from a detailed message on the website of the Nobel Committee
based on the materials of the works of Thomas Staitz laboratory staff
respectively, 1998, 1999 and 2000
Meanwhile, Venka Ramakrishnan's group, working in the Laboratory of Molecular Biology in Cambridge, obtained an equally detailed model of the small ribosome subunit of another bacterial species, and in the same year an article about it was published in Nature. Almost simultaneously, an article was published by Ada Yonat and her collaborators, who achieved almost the same result with a small subunit of the bacterial ribosome, although they made, as it turned out later, a number of mistakes in interpreting its structure.
A model of the structure of the whole ribosome (that is, a complex of large and small subunits and transport RNA molecules, or tRNAs delivering amino acids to the ribosome) with a less detailed resolution (7.8 A) was first obtained in 1999 in the laboratory of Harry Knoller (Harry F. Noller) from the University of California at Santa Cruz with the participation of Marat and Gulnara Yusupov, who were already working for Noller at that time.
Noller (photo from the website soe.ucsc.edu ) led the group that prepared the first model of the structure of the whole ribosome, and did a lot to understand the structure of ribosomes and the mechanism of protein synthesis, but was not among the laureates of the Nobel Prize awarded for research on the structure and work of ribosomes.
The 1999 publication was followed by another one, in 2001, in which the structure of the whole ribosome was described with a resolution of 5.5 A, that is, close to atomic. Subsequently, several laboratories, including Noller's laboratory, managed to obtain models of the structure of the whole ribosome and with atomic resolution. The first such model (with a resolution of 3.5 A) was presented by a group led by Jamie H.D. Cate from the University of California at Berkeley.
About two–thirds of the ribosome mass is RNA, and about a third is proteins. Studies of the structure and work of ribosomes have shown that the functional load in ribosomes is primarily carried by RNA. Thus, ribosomes are, in fact, giant ribozymes. This discovery speaks in favor of the hypothesis that at the first stages of the existence of life, it represented the "world of RNA": RNA molecules provided both the storage of hereditary information and the management of chemical processes necessary for reading and reproducing this information; subsequently, these functions were transferred to DNA and proteins, respectively, during evolution.
Ideas about the structure of ribosomes are also directly applied in practice. Many antibiotics used to treat infectious diseases act by suppressing the work of bacterial ribosomes. In the laboratories of Yonat, Ramakrishnan and Staitz, data on the mechanism of action of a number of such antibiotics were obtained. These data are already being used today to develop new and improve existing antibiotics. This task is very relevant, since pathogenic bacteria are continuously evolving, developing resistance to the drugs used in medical practice, and pharmaceuticals cannot lag behind bacteria in this continuous "arms race".
Simplified scheme of ribosome operation (left) and its blocking by an antibiotic (right).
Information RNA (RNA) is synthesized on the DNA matrix (DNA), to which two ribosome subunits are subsequently attached and protein synthesis begins.
Each amino acid (amino acid), which is part of the protein chain, is delivered to the ribosome by a transport RNA (schematically depicted as a fork).
Some antibiotics are able to bind to bacterial ribosomes, stopping protein synthesis and leading to the death of bacterial cells.
(Illustration to an article published in the New York Times on the 2009 Nobel Prize in Chemistry.)
Each Nobel Prize can be divided into no more than three, and the choice of these three from among worthy applicants is indisputable and almost always leaves in the shadow of scientists whose contribution to the award-winning discovery also deserves recognition. So it happened this time. Peter Moore, Jamie Keith and Marat Yusupov are among those outstanding researchers of the structure of ribosomes who will not be among the recipients of this award. But especially unfair is the absence among the laureates of Harry Knoller, who was the first to show the key role of RNA in the work of ribosomes, the first to read the sequence of ribosomal RNA nucleotides and found out its secondary structure (that is, how it is folded), mapped the binding sites of most ribosome ligands, the first to establish the structure of the whole ribosome in complex with tRNA molecules – and at the same time he turned out to be the fourth extra.
Although the choice of three laureates made by the Nobel Committee can be considered controversial, the very scientific achievement for which they will be awarded is quite worthy of the Nobel Prize in Chemistry. In the course of studies of the structure of ribosomes, methods of X-ray diffraction analysis were improved, which made it possible to describe with atomic resolution the interaction of the ribosome with the proteins controlling its operation and with tRNA molecules, as well as changes occurring in the structure of the ribosome during protein synthesis. To date, ribosomes are the largest asymmetric macromolecular complexes with an established structure (the structure of viruses is easier to study due to their symmetry). It can be expected that in the future, X-ray diffraction analysis will be successfully applied to study the structure and operation of other large macromolecular complexes, for example, spliceosomes, which cut out non-coding sequences (introns) from the precursors of informational RNA.
Main sources:
Richard Van Noorden. Ribosome clinches the chemistry Nobel // Nature News. Published online 7 October 2009.
Robert F. Service. 2009 Chemistry Nobel honors work on ribosomes // ScienceNOW Daily News. Published online 7 October 2009.
The Nobel Prize in Chemistry 2009 (message on the website of the Nobel Committee).
See also:
Elizabeth Pennisi. The race to the ribosome structure // Science. 24 September 1999. V. 285. P. 2048–2051.
Nobel Prize in Chemistry – 2008, "Elements", 11.10.2008.
Portal "Eternal youth" http://vechnayamolodost.ru
15.10.2009