The Spectacular Ribosomal Architecture: Nascent Proteins Voyage Towards Folding via Antibiotics Binding-pockets

Ada E. Yonath 

Weizmann Institute, Structural Department, Rehovot 76100, Israel

Abstract

Ribosomes position their substrate at stereochemistry suitable for peptide bond formation and for substrate-mediated chemical catalysis. Their active site is located within a universal internal symmetrical region, which connects all ribosomal features involved in its functions, hence can transfer intra-ribosomal signals between them. The symmetry relates RNA backbone and nucleotides orientation but shows no sequence homology, thus demonstrating the superiority of the functional requirements over sequence conservation, and suggesting that ribosomes evolved by gene-fusion.

The linkage between substrate positioning and the symmetrical region indicates a guided rotatory motion of the aminoacylated-tRNAs along a path created by the ribosome, which enables ribosomal polymerase action, and advances the nascent chain into the exit tunnel at an extended conformation. This tunnel was shown to possess significant dynamics that facilitate its interactive participation in gating, elongation arrest, discrimination and cellular signaling. Likewise, initial steps in chaperon-aided folding are associated with the mobility of the first chaperone to encounter the emerging polypeptides, named trigger factor in eubacteria. Adjacent to the tunnel is a crevice to which a hydrophobic compound that could mimic a secondary structure element binds selectively, thus indicating a possible cotranslational chaperoning role of the ribosome.

Structures of over a dozen antibiotics complexes, obtained at clinically relevant concentrations with ribosomes of eubacteria suitable to serve as pathogen models, illuminated the fundamental principles of antibiotics inhibitory action, provided the structural basis for antibiotics selectivity, and revealed the molecular mechanisms of antibiotics resistance. Comparison to antibiotics complexed with ribosomes from an archaeon that shares properties with eukaryotes, and its mutant, allowing antibiotics binding, illuminated structural elements required for therapeutical effectiveness and indicated that optimal antibiotics binding may require drug's conformational rearrangements. It also showed that whereas the identity of a single nucleotide determines drug's binding, the proximal nucleotides govern the binding-modes and, consequently, the clinical effectiveness.

 

Presentation: plenary lecture at 18th Conference on Physical Organic Chemistry, Plenary session, by Ada E. Yonath
See On-line Journal of 18th Conference on Physical Organic Chemistry

Submitted: 2006-05-22 20:26
Revised:   2009-06-07 00:44