The aim of the project is to understand key steps in the molecular mechanisms of protein synthesis across species. The structure and function of pro- and eukaryotic (including human) ribosomes, those cellular nano-machineries that catalyse the decoding of genes, will be studied through an integrative, interdisciplinary structural biology approach. Since in the cell the ribosome is regulated by transiently binding protein and RNA factors, we plan the reconstitution and structural investigation of ribosome complexes in functionally defined states with regulatory proteins and messenger RNAs (mRNA). Four work packages will form the basis of the investigation, (i) the role of mRNA structure in gene expression in pro- and eukaryotes, (ii) the mechanism of translation initiation in prokaryotes as important antibiotic targets, (iii) the high-resolution structure of the human ribosome, and (iv) the architecture of eukaryotic polysomes, the functional protein synthesis entities of living cells. The complexes will be studied using a comprehensive approach which will incorporate biochemistry, structural biology, biophysics and bio-informatics, with cryo-electron microscopy and X-ray crystallography forming the core. The dynamic aspects of the protein synthesis machinery such as structural and functional transitions will be investigated by separation of multiple states through advanced image processing procedures, molecular dynamics simulations and by exploring new developments in optical imaging. Collaborations with leading laboratories have been set up in order to create an efficient framework for which the host institute provides an outstanding infrastructure. The project will provide fundamental knowledge on the mechanism of gene expression regulation at the level of protein synthesis contributing in the long term to the development of new drugs.
Fields of science
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