Ribosomal Crystallography: Peptide Bond Formation, Chaperone Assistance, and Antibiotics Inactivation

The peptidyl transferase center (PTC) is an arched void has dimensions suitable for accommodating the 3′ ends of the A-and the P-site tRNAs. It is situated within a universal sizable symmetrical region that connects all ribosomal functional centers involved in aminoacid polymerization. The linkage between the elaborate PTC architecture and the A-site tRNA position revealed that the Ato P-site passage of the tRNA 3′ end is performed by a rotatory motion, which is synchronized with the overall tRNA/mRNA sideways movement, and leads to stereochemistry suitable for peptide bond formation and for substrate mediated catalysis, thus suggesting that the PTC evolved by gene fusion. Adjacent to the PTC is the entrance of the protein exit tunnel, shown to play active roles in sequence-specific gating of nascent chains and in responding to cellular signals. This tunnel also provides a site that may be exploited for local cotranslational folding and seems to assist nascent chain trafficking into the hydrophobic space formed by the first bacterial chaperone, the trigger factor. Many antibiotics target ribosomes. Although the ribosome is highly conserved, subtle sequence and/or conformational variations enable drug selectivity, thus facilitating clinical usage. Comparisons of high-resolution structures of complexes of antibiotics bound to ribosomes from eubacteria resembling pathogens, to an archaeon that shares properties with eukaryotes and to its mutant that allows antibiotics binding, demonstrated the unambiguous difference between mere binding and therapeutical effectiveness. The observed variability in antibiotics inhibitory modes, accompanied by the elucidation of the structural basis to antibiotics mechanism justifies expectations for structural based improved properties of existing compounds as well as for the development of novel drugs.