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 ribosome and its interactions with messenger RNA, transfer RNA and the protein synthesis factors. This proposal aims to obtain crystals of functional complexes of the ribosome and to solve their structures by x-ray crystallography. These results will be combined with knowledge of ribosome function obtained from biochemical, biophysical and genetic approaches to reconstruct a dynamic, three-dimensional description of the process of 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|
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|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|
|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|
|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|
|Zhou, Jie; Lancaster, Laura; Trakhanov, Sergei et al. (2012) Crystal structure of release factor RF3 trapped in the GTP state on a rotated conformation of the ribosome. RNA 18:230-40|
|Zhou, Jie; Korostelev, Andrei; Lancaster, Laura et al. (2012) Crystal structures of 70S ribosomes bound to release factors RF1, RF2 and RF3. Curr Opin Struct Biol 22:733-42|
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