Hibernating Bears, Antibiotics, and the Evolving Ribosome (Nobel Lecture)

Abstract

High-resolution structures of ribosomes, the cellular machines that translate the genetic code into proteins, revealed the decoding mechanism, detected the mRNA path, identified the sites of the tRNA molecules in the ribosome, elucidated the position and the nature of the nascent proteins exit tunnel, illuminated the interactions of the ribosome with non-ribosomal factors, such as the initiation, release and recycling factors, and provided valuable information on ribosomal antibiotics, their binding sites, modes of action, principles of selectivity and the mechanisms leading to their resistance. Notably, these structures proved that the ribosome is a ribozyme whose active site, namely where the peptide bonds are being formed, is situated within a universal symmetrical region that is embedded in the otherwise asymmetric ribosome structure. As this symmetrical region is highly conserved and provides the machinery required for peptide bond formation and for ribosome polymerase activity, it may be the remnant of the proto-ribosome, a dimeric prebiotic machine that formed peptide bonds and non-coded polypeptide chains. Structures of complexes of ribosomes with antibiotics targeting them revealed the principles allowing for their clinical use, identified resistance mechanisms and showed the structural bases for discriminating pathogenic bacteria from hosts, hence providing valuable structural information for antibiotics improvement and for the design of novel compounds that can serve as antibiotics.

Comparative Visualization of the RNA Suboptimal Conformational Ensemble In Vivo

“…Generally, however, the functions of structures in messenger RNAs are poorly understood, except for a few cases, such as the iron responsive element (22, 70) and the histone stem loop (71, 72, 73), in which single structures are essential for function. Other than ribosomal RNA, no RNA larger than 1 kb, including mRNAs, is known to fold into a unique, well-defined conformation (65, 67, 68, 69, 74, 75).…”

Ribozyme Activity of RNA Nonenzymatically Polymerized from 3′,5′-Cyclic GMP

“…This mechanism potentially represents a plausible means to generate RNA sequence complexity and to approach the question: how could the extremely complex ribosomal machinery [31] start to evolve and how did the initial RNA transfer functions [32] come about?…”

Anti-plasmodial action of de novo-designed, cationic, lysine-branched, amphipathic, helical peptides

“…The success of antibiotics is based upon the characteristic molecular targets that distinguish the prokaryotic bacteria from the nucleated eukaryotic cells [32,33]. Cationic, amphipathic helical, antibiotic peptides also seem to gain specificity by exploiting the fact that bacteria have a preponderance of anionic lipids, such as phosphatidylglycerol and bis(phosphatidyl)glycerol (cardiolipin), conferring a negative charge on their surface.…”