Ribosomes are the molecular complexes that are responsible for translation of the genetic code and synthesis of proteins in all living cells. The ultimate goal of this project is to obtain an understanding of protein synthesis in terms of the structures and dynamics of the ribosome and its interactions with messenger RNA, transfer RNA and the protein synthesis factors. This proposal aims to use biochemical and biophysical methods, including chemical probing, directed mutagenesis, fluorescence resonance energy transfer (FRET) and optical tweezers approaches, to observe ribosome movement both in bulk and on the single-ribosome scale. These results will be combined with knowledge of the three-dimensional structure of the ribosome to reconstruct the molecular dynamics of the ribosome during protein synthesis.
Since bacterial ribosomes are the targets of many powerful antimicrobial antibiotics, a deeper understanding of their structure and function will help to design new drugs to combat the increasing problem of drug-resistant pathogenic bacteria. Also of great relevance to public health is the finding that mutations in human mitochondrial ribosomes are responsible for a variety of human diseases, including deafness and cancer. Research on ribosome structure and function can improve our understanding of how these molecular defects lead to disease, providing a solid basis for devising approaches to design of therapies.
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