Biomedical Implications of Ribosome Research Harry Noller, MCD Biology Ribosomes are RNA-based molecular machines that are responsible for synthesis of proteins. Researchers in the Noller laboratory were the first to solve the complete structure of a ribosome using X-ray crystallography. Besides the importance of protein synthesis to understanding the molecular basis of cellular function, research on ribosomes promises to improve the design of new antibiotics. Many of today's most effective anti-microbial drugs work by targeting bacterial ribosomes. As pathogenic bacteria continue to develop resistance to commonly used antibiotics, clarification of the structure and molecular mechanisms of bacterial ribosomes will be critical for the design of new drugs that will keep pace with rapidly evolving bacteria. (Keywords: RNA, ribosome, rRNA, tRNA, translation, protein synthesis, crystallography, FRET, structural biology, crystallography)

Protein Synthesis

In all living organisms, proteins are specified by genes, which are encoded in the nucleotide sequences of their DNA. To synthesize a protein, the DNA sequence of the gene is first transcribed into a messenger RNA (mRNA), and the nucleotide sequence of the mRNA is then translated by the ribosome into protein. The ribosome is therefore a type of readout device, not unlike a tape player. It transforms the stored DNA/RNA information from the language of the four nucleotides (A,G,C and U or T) into the final product Ð the protein Ð whose structure is written in the language of the twenty different amino acids. Each of the amino acids in the protein sequence is specified by a sequence of three nucleotides in the mRNA called a codon. For example, the codon AUG specifies the amino acid methionine.

The ribosome uses adapters called transfer RNAs (tRNAs) to recognize each codon by base pairing of a three-nucleotide sequence in the tRNA, called an anticodon, with the codon. Each tRNA brings in a specific amino acid in response to its cognate codon in the mRNA. The ribosome then links the amino acids together into the protein chain. During readout of the mRNA, the mRNA and tRNAs are moved through the ribosome, as the newly created protein emerges.

The three-dimensional structure of the complete 70S ribosome from the bacterium Thermus thermophilus at 3.7 Å resolution (Korostelev et al., 2006).

The Ribosome

Ribosomes are among the most complex molecular assemblies in the cell. The simplest ribosomes, for example those of bacteria, have a molecular weight of about 2.5 million Daltons, comprising the very large 16S and 23S ribosomal RNAs (rRNAs), 5S rRNA and more than 50 different proteins. Researchers in the Noller laboratory have solved the structure of the complete 70S ribosome from the bacterium Thermus thermophilus using X-ray crystallography. The folding of the rRNAs, the locations of the ribosomal proteins, and the locations of the mRNA and tRNAs in the 70S ribosome can be seen for the first time.

Ribosome Research will Impact the Design of Antibiotics

Besides the importance of protein synthesis to understanding the molecular basis of cellular function, research on ribosomes has paved the way to understanding how antibiotics work. Many of the most effective anti-microbial antibiotics, such as erythromycin, neomycin, spectinomycin, tylosin and tetracycline, work by targeting bacterial ribosomes, interfering with functions such as tRNA recognition, movement of tRNA through the ribosome (translocation), or joining the amino acids together (peptidyl transferase). However, in recent years, pathogenic bacteria have evolved a variety of mechanisms to become resistant to almost all of the commonly used antibiotics, which has led to a world-wide resurgence in serious illnesses caused by bacterial infections. An increased understanding of how the ribosome works, together with knowledge of its three-dimensional molecular structure, are now leading to strategies for the design of novel antibiotics.