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.
| Noller, Harry F (2017) The parable of the caveman and the Ferrari: protein synthesis and the RNA world. Philos Trans R Soc Lond B Biol Sci 372: |
| Mohan, Srividya; Noller, Harry F (2017) Recurring RNA structural motifs underlie the mechanics of L1 stalk movement. Nat Commun 8:14285 |
| Colussi, Timothy M; Costantino, David A; Zhu, Jianyu et al. (2015) Initiation of translation in bacteria by a structured eukaryotic IRES RNA. Nature 519:110-3 |
| Mohan, Srividya; Donohue, John Paul; Noller, Harry F (2014) Molecular mechanics of 30S subunit head rotation. Proc Natl Acad Sci U S A 111:13325-30 |
| Zhou, Jie; Lancaster, Laura; Donohue, John Paul et al. (2014) How the ribosome hands the A-site tRNA to the P site during EF-G-catalyzed translocation. Science 345:1188-91 |
| Liu, Tingting; Kaplan, Ariel; Alexander, Lisa et al. (2014) Direct measurement of the mechanical work during translocation by the ribosome. Elife 3:e03406 |
| Noller, Harry F (2013) How does the ribosome sense a cognate tRNA? J Mol Biol 425:3776-7 |
| Zhou, Jie; Lancaster, Laura; Donohue, John Paul et al. (2013) Crystal structures of EF-G-ribosome complexes trapped in intermediate states of translocation. Science 340:1236086 |
| Santos, Natalia; Zhu, Jianyu; Donohue, John Paul et al. (2013) Crystal structure of the 70S ribosome bound with the Q253P mutant form of release factor RF2. Structure 21:1258-63 |
| Ramrath, David J F; Lancaster, Laura; Sprink, Thiemo et al. (2013) Visualization of two transfer RNAs trapped in transit during elongation factor G-mediated translocation. Proc Natl Acad Sci U S A 110:20964-9 |
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