Goals: The long-term goal of our project is to shed light on the molecular mechanism of protein biosynthesis. Ribosomes are the universal cell organelles facilitating the translation of the genetic code into proteins. These nucleoprotein assemblies (mw 2.3 mega-Dalton, about 4500 RNA nucleotides and 75 proteins) are built of two subunits of unequal size (0.85 and 1.45 mega-Dalton), which associate upon the initiation of protein biosynthesis. The immediate objectives of this proposal are (a) to use the high-resolution structures of the two eubacterial ribosomal subunits determined by us as references for the elucidation of the structures of ribosomal complexes with substrate analogs, functional ligands, inhibitors and antibiotics; (b) to exploit these structures for illuminating the mechanisms involved in peptide bond formation, decoding, translocation, inhibition by and resistance to antibiotics; (c) to progress toward high resolution structure determination of complexes capturing the whole ribosome at defined functional states; (d) to advance towards the determination of the structure of eukaryotic ribosomes. Methods: Highly active ribosomes from robust organisms are being crystallized. X-ray diffraction data are being collected at cryogenic temperatures from flash-frozen crystals, using state-of-the-art high brilliance synchrotron radiation. Phases are being determined by a combination of MIRAS, molecular replacement and crystal averaging, and used to locate the bound ligands and antibiotics in difference electron density maps. The significance of ribosomal crystallography stems from its potential to illuminate the mechanism of a fundamental life process, protein biosynthesis. The already known structures revealed the modes of action of several antibiotic agents that target the ribosome, illuminated principles of drug selectivity, and provided significant basic knowledge of possible pathways of drug resistance. These, and further to come insights, should lead to improved therapeutic agents and allow structure based design of a new generation of more powerful, selective and efficient antibiotics.
| Krupkin, Miri; Wekselman, Itai; Matzov, Donna et al. (2016) Avilamycin and evernimicin induce structural changes in rProteins uL16 and CTC that enhance the inhibition of A-site tRNA binding. Proc Natl Acad Sci U S A 113:E6796-E6805 |
| Auerbach-Nevo, Tamar; Baram, David; Bashan, Anat et al. (2016) Ribosomal Antibiotics: Contemporary Challenges. Antibiotics (Basel) 5: |
| Belousoff, Matthew J; Shapira, Tal; Bashan, Anat et al. (2011) Crystal structure of the synergistic antibiotic pair, lankamycin and lankacidin, in complex with the large ribosomal subunit. Proc Natl Acad Sci U S A 108:2717-22 |
| Krupkin, Miri; Matzov, Donna; Tang, Hua et al. (2011) A vestige of a prebiotic bonding machine is functioning within the contemporary ribosome. Philos Trans R Soc Lond B Biol Sci 366:2972-8 |
| Auerbach, Tamar; Mermershtain, Inbal; Davidovich, Chen et al. (2010) The structure of ribosome-lankacidin complex reveals ribosomal sites for synergistic antibiotics. Proc Natl Acad Sci U S A 107:1983-8 |
| Yonath, Ada (2010) Polar bears, antibiotics, and the evolving ribosome (Nobel Lecture). Angew Chem Int Ed Engl 49:4341-54 |
| Davidovich, Chen; Belousoff, Matthew; Wekselman, Itai et al. (2010) The Proto-Ribosome: an ancient nano-machine for peptide bond formation. Isr J Chem 50:29-35 |
| Belousoff, Matthew J; Davidovich, Chen; Zimmerman, Ella et al. (2010) Ancient machinery embedded in the contemporary ribosome. Biochem Soc Trans 38:422-7 |
| Davidovich, Chen; Belousoff, Matthew; Bashan, Anat et al. (2009) The evolving ribosome: from non-coded peptide bond formation to sophisticated translation machinery. Res Microbiol 160:487-92 |
| Wekselman, Itai; Davidovich, Chen; Agmon, Ilana et al. (2009) Ribosome's mode of function: myths, facts and recent results. J Pept Sci 15:122-30 |
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