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Structural Basis of Protein Synthesis System of Human Cell

Final Report Summary - SBPSSHS (Structural Basis of Protein Synthesis System of Human Cell)

The aim of our application was development of the structural basis of the protein synthesis system of the human cell. Realization of the project was divided on two steps. First part of the project was focused on structure determination of the ribosome from Saccharomyces cerevisiae and structures of functional complexes of this ribosome. For realization of second part of the project as structure determination of human ribosome we have to use knowledge of biochemical properties and crystallization abilities of yeast ribosome and other eukaryotes. We have determined atomic resolution crystal structure of yeast ribosome. This is first eukaryotic 80S ribosome structure interpreted at 3.0 Å resolution containing both ribosomal subunits 40S and 60S with 80 individual proteins and near 5500 nucleotides of ribosomal RNA in total. Comparison of bacterial and yeast ribosome structures have shown conservative core of the ribosome responsible for major functions as tRNA and mRNA binding, organization of decoding center and organization of peptidyl-transferase center. (Ben-Shem, Science, 2011). We have determined 16 different X-ray structures of eukaryotic ribosome with inhibitors. These are small natural metabolites which can inhibit protein synthesis by binding to the ribosomal functional site and disturbing ribosomal function. Interaction of inhibitor with flexible domains of the ribosome increases stability and homogeneity of the complex and can be a useful tool in crystallization experiments. It was shown that 12 studied inhibitors are eukaryote specific and cannot bind to bacterial ribosome. The mechanism how inhibitor can distinguish between bacteria and yeast ribosome was explained. (Garreau de Loubresse, Nature, 2014).