Stem Cells, Vol. 19, No. 1, 92-93,
January 2001
© 2001 AlphaMed Press
FUNDAMENTALS OF CANCER MEDICINE |
The Molecular Perspective: The Ribosome
David S. Goodsell
David S. Goodsell, Ph.D., The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail: goodsell{at}scripps.edu WorldWideWeb:http://www.scripps.edu/pub/goodsell
In cells, proteins perform nearly every task. Cells contain protein motors and protein messengers, efficient catalysts made of protein, protein supertankers to deliver materials and protein highways to guide this delivery. Cells devote most of their resources to synthesis of these diverse macromolecular machines. However, the factory that constructs all of these proteins is composed, quite ironically, not of protein, but primarily of RNA. The ribosome, pictured in Figure 1
, is built largely of RNA, and there is strong structural evidence that a specific adenine base, which is activated by a magnesium ion, forms each new peptide bond as the protein chain grows. The unusual nature of the ribosome may be a fossil of evolution, preserved from a time when life was based primarily on nucleic acids, before the reign of proteins.
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Figure 1. Atomic structure of the ribosome. The ribosome is composed of two subunits, which clamp around a messenger RNA during protein synthesis. In this illustration, the two subunits are separated and rotated so that the face that interacts with messenger RNA is exposed. These structures are of bacterial ribosomes —our own ribosomes are somewhat larger. Ribosomes are composed primarily of RNA, shown here in orange and yellow, decorated by a collection of small proteins, shown in blue. The small subunit, shown on the right, matches each messenger RNA codon with the proper transfer RNA anticodon. The messenger RNA is thought to thread through the small hole on the left edge, and then extend along the groove horizontally. The large subunit, shown on the left, performs the synthesis reaction, removing the amino acid from the transfer RNA and adding it to the new protein. The putative catalytic adenine is shown in green. The protein D-alanyl-D-alanine peptidase, a typically sized enzyme which performs a similar peptide-forming reaction, is shown at the same magnification at the center for comparison. The ribosome structures are taken from entries 1ffk and 1fka and the peptidase is from entry 1cef at the Protein Data Bank (http://www.rcsb.org/pdb).
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As you can see, the ribosome is an enormous molecular machine, approaching small viruses in size. The small protein D-alanyl-D-alanine peptidase (the target of penicillin in bacterial cells, also shown in Fig. 1
) performs a similar catalytic task, but with a fraction of the molecular overhead. The difference, of course, is that the ribosome performs an "information-driven" synthesis, whereas the small peptidase can perform only one specific peptide-forming reaction. The ribosome is universal: it can take any set of instructions, encoded in messenger RNA, and build a protein chain according to the blueprint. To allow this marvelous generality, the ribosomal machinery must be far more complex than most simple enzymes.
As with most essential mechanisms in the cell, you can find a wide selection of natural toxins to attack the ribosome. Small molecules such as streptomycin, tetracycline and chloramphenicol interfere with the small ribosomes of bacteria, and thus are useful as antibiotics. Ricin, an enzyme from castor bean, is phenomenally toxic. It clips off a specific adenine base, inactivating the large subunit of eukaryotic ribosomes. Unlike typical drugs, which must bind one-to-one with their targets, ricin can jump from ribosome to ribosome, inactivating each in turn. A single molecule can be enough to kill an entire cell.
Unfortunately, these "super-toxins" present grave problems when used for anti-cancer therapy. Cells are sensitive to mutations in their vital mechanisms, so cancer ribosomes are identical with the ribosomes in healthy cells. You might imagine that this yields no leeway for cancer therapy, because ricin efficiently kills both normal and cancerous cells. However, clever chemists have devised a solution that allows use of these amazing toxins, in the form of immunotoxins, which will be discussed in the next issue.
ADDITIONAL READING
- Nissen P, Hansen J, Ban N et al. The structural basis of ribosome activity in peptide bond synthesis. Science 2000;289:920-930.
- Puglisi JD, Blanchard SC, Green R. Approaching translation at atomic resolution. Nat Struct Biol 2000;7:855-861.
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Figure 2. The ribosome in action. The two subunits of the ribosome (shown in red) clamp around a snake-like messenger RNA (in white) and step down it, one codon at a time, building a new protein based on the encoded information. Scattered through the cytoplasm, many other molecules are needed (shown in yellow and orange), including transfer RNA and aminoacyl-tRNA synthetases, a collection of initiation, elongation and termination factors, and chaperones to help new proteins fold properly.
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