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

Nature volume 413, pages 814–821 (2001)Cite this article

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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Figure 1: Interaction of chloramphenicol with the peptidyl transferase cavity.
Figure 2: Interaction of clindamycin with the peptidyl transferase cavity.
Figure 3: Interaction of macrolides with the peptidyl transferase cavity.
Figure 4: Relative position of chloramphenicol, clindamycin and macrolides with respect to CC-puromycin and the 3′-cytosine-adenine (CA) end of P-site and A-site tRNAs.
Figure 5: Top view of the D. radiodurans 50S subunit showing erythromycin (red) bound at the entrance of the tunnel.

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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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  1. Frank Schlünzen, Raz Zarivach, Jörg Harms, Ante Tocilj, Renate Albrecht and François Franceschi: These authors contributed equally to this work

Authors and Affiliations

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

    Frank Schlünzen, Jörg Harms, Ante Tocilj & Ada Yonath

  2. Department of Structural Biology, Weizmann Institute, Rehovot, 76100, Israel

    Raz Zarivach, Anat Bashan & Ada Yonath

  3. Max-Planck-Institut für Molekulare Genetik, Ihnestrasse 73, Berlin, 14195, Germany

    Ante Tocilj, Renate Albrecht & François Franceschi

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Correspondence to François Franceschi.

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Schlünzen, F., Zarivach, R., Harms, J. et al. Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria. Nature 413, 814–821 (2001). https://doi.org/10.1038/35101544

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