Ribosome insight could help combat antibiotic resistance

May 03, 2001

ARGONNE, IL (May 4, 2001) - Researchers from the United Kingdom have come to Argonne's Advanced Photon Source to take a close look at one of the cell's most important players, the protein factory called the ribosome. What they found offers new information on how proteins are formed and how they create the chain of proteins that make up an organism.

A detailed picture of how the ribosome allows accurate translation of the genetic code has been obtained by a team of Medical Research Council biologists and it could play a significant role in understanding how many antibiotics work.

The ribosome is the large molecular machine in all cells that makes proteins (the building blocks of organisms) by translating the information encoded by genes.

In a paper published in Science today, the team from the Medical Research Council Laboratory of Molecular Biology provides insight into how ribosomes manufacture proteins from amino acids to the exact specification of the genes on DNA. The work has also shown previously unknown details of how antibiotics actually work and how an antibiotic could induce a ribosome to make a "mistake" and allow the wrong amino acid to be added onto the protein chain. Such incorrectly-made proteins wouldn't function so if this happened in bacteria during development they would be rendered ineffective.

Dr. Venki Ramakrishnan, head of the Laboratory of Molecular Biology, explained: "As biologists we are fascinated by these results because of their fundamental importance in understanding how the genetic code gets translated into proteins. However, pharmaceutical and biotech companies are keenly interested because this research not only helps us to understand how many known antibiotics work but also helps us to understand the basis of certain kinds of resistance. This will hopefully allow us to design new antibiotics in the future that can overcome the growing world-wide problem of resistance."

The ribosome binds to a molecule called messenger RNA, which is a copy of the gene on DNA. Other RNA molecules - transfer RNA (tRNA) - bind to the ribosome. At one end a short strand is complementary to the code on the messenger RNA. The other end brings in the new amino acid to be attached. The ribosome's role is to ensure that the "correct" tRNA (i.e. as specified by the code from the messenger RNA) is accepted and the wrong ones are rejected. Once the tRNA is accepted, the ribosome catalyzes the formation of a peptide bond between the growing protein chain and the new amino acid, lengthening it by one. The process stops when the end of the gene is reached.

The ribosome consists of two halves - a small or "30S" subunit which binds messenger RNA and a large or "50S" subunit that catalyses the peptide bond. Bacteria and human ribosomes are different and as a result, a large number of antibiotics have evolved naturally that bind to and block bacterial ribosomes more effectively than they do human ribosomes.

Dr Ramakrishnan continued: "Although these antibiotics were discovered several decades ago, we haven't understood in detail how they work."

Recently, several groups of researchers have been developing high resolution three-dimensional structure of both subunits of the ribosome by using macromolecular X-ray crystallography. A group at Yale University solved the structure of the 50S subunit. Two groups have worked on the 30S subunit, one at the Max Planck Institute in Germany and the Weizmann Institute in Israel, headed by Ada Yonath and a second at the Medical Research Council Laboratory of Molecular Biology headed by Dr Ramakrishnan. The U.K. group has previously solved the atomic structure of the 30S subunit and its complex with several different antibiotics. These results were published in Nature in September last year and in Cell in December. The paper being published today describes how the group has solved the structure of the 30S subunit with a piece of mRNA and tRNA, both in the presence and absence of a different antibiotic, paromomycin. The work shows how the ribosome recognises that the tRNA bound is "correct" and matches the code specified by the messenger RNA, which is in turn a copy of the gene, and how antibiotics could allow the ribosome to accept incorrect tRNAs and allow the wrong amino acid to be added on to the protein chain.

Argonne's Advanced Photon Source produces the nation's most brilliant X-rays for research. The facility, which opened in 1996, is funded by the U.S. Department of Energy's Office of Basic Energy Sciences. The research reported today was funded by the Medical Research Council in the U.K. and the U.S. National Institutes of Health.

The British researchers are the most recent of a long series of groups of scientists who are using the facilities of the Structural Biology Center at the Advanced Photon Source to develop crystal structures of various portions of the ribosome. The Structural Biology Center provides the latest in instruments and other equipment for X-ray crystallography, a specialized research method for determining the molecular structure of materials.
The Medical Research Council is the U.K. government's leading agency which supports research into all areas of medical science, through its own research facilities and by providing grants to individual scientists and support for postgraduate students. The Laboratory of Molecular Biology is part of that organization.

America's first national laboratory, Argonne is operated by the University of Chicago as part of the U.S. Department of Energy's national laboratory system.

Media Contact:
Marion Irving
Medical Research Council, UK

DOE/Argonne National Laboratory

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