Ada Yonath
Department of Structural Biology, Weizmann Institute, Rehovot 76100
Ribosomes, the universal cellular machines for translation of the genetic code into proteins, possess spectacular architecture accompanied by inherent mobility, allowing for their smooth performance as polymerases that translate the genetic code into proteins. The site for peptide bond formation is located within a universal internal semi-symmetrical region. The high conservation of this region implies its existence irrespective of environmental conditions and indicates that it may represent an ancient RNA machine. Hence, it could be the kernel around which life originated. The mechanistic and genetic applications of this finding will be discussed
Owing to the key role played by ribosomes in life cycles, almost half of the clinically useful antibiotics paralyze ribosomes by binding to their functional sites. By investigating the three dimensional structures of ribosomes from nonpathogenic bacteria as models for genuine pathogens, common features were identified. Thus, the antibiotics binding modes, inhibitory actions and synergism pathways have been determined for almost all ribosomal antibiotics. These indicated the principles of differentiation between patients and pathogens and suggested common principles of mechanisms leading to bacterial resistance.
The incredible global increase in resistance to antibiotics that we are witnessing recently is a serious medical threat. It seems that the world is approaching a post-antibiotic era, in which common infections and minor injuries that have been treatable for decades could become fatal once again.
As species specific diversity was detected in susceptibility to infectious diseases and in developing specific resistance mechanisms, our structural studies have been extended to ribosomes from genuine pathogens. By determining the high resolution structure of the first and only ribosomal particle from a genuine pathogen with several antibiotics, we identified subtle, albeit highly significant structural elements that can account for the species specificity in resistance, thus could paved ways for improvement of existing antibiotics as well as for the design of advanced therapeutics capable of minimizing antibiotics resistance.