The spectacular ribosomal architecture: From protein making to folding via the antibiotics binding pocket
Ada Yonath

The spectacular ribosomal architecture: From protein making to folding via the antibiotics binding pocket

Ada Yonath, Weizmann Institute of Science, Rehovot, Israel

Ribosomes position their substrate at stereochemistry suitable for peptide bond formation, and for promoting substrate-mediated catalysis. Substrate orientation is dominated by remote interactions, and the linkage between it and a sizable symmetrical region identified in all known ribosome structures, indicates a guided rotatory motion of aminoacylated-tRNAs along a path created by the ribosome. This rotatory motion enables ribosomal polymerase action, and advances the nascent chain into the exit tunnel at an extended conformation. This symmetry relates RNA backbone and nucleotides orientation, but shows no sequence homology, demonstrating the superiority of the functional requirements over sequence conservation, and suggesting that ribosomes evolved by gene-fusion. The symmetrical region can transfer intra-ribosomal signals as it connects, directly or by its extensions, all ribosomal functional elements, including peptide-bond-formation and decoding sites, the tRNA entrance and exit points and the protein exit tunnel entrance. This tunnel, thought to be a passive path, was shown to possess significant dynamic properties that facilitate its interactive participation in gating, elongation arrest, discrimination and cellular signaling. Likewise, the initial steps in chaperon-aided folding are associated with significant mobility of the first chaperone to encounter the emerging polypeptides, named trigger factor in eubacteria.
Structures of over a dozen antibiotics complexes, obtained at clinically relevant concentrations with eubacterial ribosomes from Deinococcus radiodurans, proved to be suitable pathogen models, illuminated the fundamental principles of antibiotics inhibitory action, provides the structural basis for antibiotics selectivity, and revealed the molecular mechanisms of antibiotics resistance.
Comparative analysis was performed between antibiotics complexed with the above mentioned eubacterial pathogen model, with ribosomes from Haloarcula marismortui, an archaeon that shares properties with eukaryotes, and with its mutant that allows antibiotics binding. The results of these comparisons illuminated the structural elements required for therapeutical usage, indicated that optimal antibiotics action may be accompanied by deviation from the drug conformation in ribosome-free environments. It was also shown that whereas identity of a single nucleotide determines whether binding occurs, the conformations of the proximal nucleotides govern the antibiotics binding-modes and, consequently their clinical effectiveness.