Ribosome: an Ancient Cellular Nano-Machine for Genetic Code Translation

Abstract

The ribosome is a ribozyme whose active site, the peptidyl trans-ferase center (PTC), is situated within a highly conserved universal symmetrical region that connects all ribosomal functional centers involved in amino-acid polymerization. The linkage between this elaborate architecture and A-site tRNA position revealed that the A- > P-site passage of the tRNA terminus in the peptidyl-transferase center is performed by a rotatory motion, synchronized with the overall tRNA/mRNA sideways movement. Guided by the PTC the rotatory motion leads to stereochemistry suitable for peptide bond formation as well as for substrate mediated catalysis, consistent with quantum mechanical calculations illuminating the transition state mechanism for peptide bond formation and indicating that the peptide bond is being formed during the rotatory motion. Analysis of substrate binding modes to inactive and active ribosomes illuminated the significant of PTC mobility and supported the hypothesis that the ancient ribosome produced single peptides bonds and non-coded chains, utilizing nucleotide conjugated amino acids. Genetic control of the reaction evolved after polypeptides capable of enzymatic function were created, and an ancient stable RNA fold was converted into tRNA molecules. As the symmetry relates only the backbone fold and nucleotides orientations, but not nucleotide sequence, it emphasizes the superiority of functional requirement over sequence conservation, and indicates that the PTC has evolved by gene fusion, presumably by taking advantage of similar RNA fold structures. The increase in antibiotic resistance among pathogenic bacterial strains poses a significant health threat. Therefore, improvement of existing antibiotics and the design of advance drugs are urgently needed. Ribosomes provide binding sited for many antibiotic families, utilizing their inherent functional flexibility, which triggers induced fit mechanism by remote interactions, and facilitates antibiotics synergism as well as reshaping less suitable binding pockets, leading to clinical usefulness even for antibiotics that bind to conserved functional regions. Exploitation of the diverse properties of antibiotics binding and benefiting from the detailed structural information that keeps emerging, should result in significant antibiotics improvement.