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Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria

Nature volume 413, pages 814821 (25 October 2001) | Download Citation

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Abstract

Ribosomes, the site of protein synthesis, are a major target for natural and synthetic antibiotics. Detailed knowledge of antibiotic binding sites is central to understanding the mechanisms of drug action. Conversely, drugs are excellent tools for studying the ribosome function. To elucidate the structural basis of ribosome–antibiotic interactions, we determined the high-resolution X-ray structures of the 50S ribosomal subunit of the eubacterium Deinococcus radiodurans, complexed with the clinically relevant antibiotics chloramphenicol, clindamycin and the three macrolides erythromycin, clarithromycin and roxithromycin. We found that antibiotic binding sites are composed exclusively of segments of 23S ribosomal RNA at the peptidyl transferase cavity and do not involve any interaction of the drugs with ribosomal proteins. Here we report the details of antibiotic interactions with the components of their binding sites. Our results also show the importance of putative Mg+2 ions for the binding of some drugs. This structural analysis should facilitate rational drug design.

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Acknowledgements

We thank A. Hofmann for advice; A. Mankin and F. Triana for critical discussions; and T. Auerbach, H. Bartels, W. S. Bennett, H. Burmeister, C. Glotz, M. Glühmann, H. A. S. Hansen, M. Kessler, M. Laschever, S. Meier, J. Muessig, M. Peretz, M. Pioletti, B. Schmidt, A. Sitka, C. Stamer and A. Vieweger for contributing to different stages of these studies. These studies could not have been performed without the cooperation of the staff of the synchrotron radiation facilities at EMBL and Max Planck Gesellschaft at DESY, ID14/2&4 at EMBL/ESRF and ID19/APS/ANL. Support was provided by the Max-Planck Society, the US National Institute of Health, the German Ministry for Science and Technology and the Kimmelman Center for Macromolecular Assembly at the Weizmann Institute. A.Y. holds the Martin S. Kimmel Professorial Chair.

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Author notes

    • Frank Schlünzen
    • , Raz Zarivach
    •  & Jörg Harms

    These authors contributed equally to this work

Affiliations

  1. *Max-Planck-Research, Unit for Ribosomal Structure, Notkestrasse 85, 22603 Hamburg, Germany

    • Frank Schlünzen
    • , Jörg Harms
    • , Ante Tocilj
    •  & Ada Yonath
  2. ‡Department of Structural Biology, Weizmann Institute, 76100 Rehovot, Israel

    • Raz Zarivach
    • , Anat Bashan
    •  & Ada Yonath
  3. §Max-Planck-Institut für Molekulare Genetik, Ihnestrasse 73, 14195 Berlin, Germany

    • Ante Tocilj
    • , Renate Albrecht
    •  & François Franceschi

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https://doi.org/10.1038/35101544

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