Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

Structural insight into the quinolone–DNA cleavage complex of type IIA topoisomerases

Nature Structural & Molecular Biology volume 16, pages 667–669 (2009)Cite this article

Abstract

Type II topoisomerases alter DNA topology by forming a covalent DNA-cleavage complex that allows DNA transport through a double-stranded DNA break. We present the structures of cleavage complexes formed by the Streptococcus pneumoniae ParC breakage-reunion and ParE TOPRIM domains of topoisomerase IV stabilized by moxifloxacin and clinafloxacin, two antipneumococcal fluoroquinolones. These structures reveal two drug molecules intercalated at the highly bent DNA gate and help explain antibacterial quinolone action and resistance.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Organization and structure of the enzyme–quinolone–DNA cleavage complex of topo IV.
Figure 2: Close up of the quinolone–topo IV cleavage complex.

Similar content being viewed by others

Accession codes

Primary accessions

Protein Data Bank

References

  1. Schoeffler, A.J. & Berger, J.M. Q. Rev. Biophys. 41, 41–101 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Drlica, K. & Zhao, X. Microbiol. Mol. Biol. Rev. 61, 377–392 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Higgins, P.G., Fluit, A.C. & Schmitz, F.J. Curr. Drug Targets 4, 181–190 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Leo, E. et al. J. Biol. Chem. 280, 14252–14263 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Drlica, K., Malik, M., Kerns, R.J. & Zhao, X. Antimicrob. Agents Chemother. 52, 385–392 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Hooper, D.C. Lancet Infect. Dis. 2, 530–538 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Laponogov, I. et al. PLoS One 2, e301 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Corbett, K.D., Schoeffler, A.J., Thomsen, N.D. & Berger, J.M. J. Mol. Biol. 351, 545–561 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Morais Cabral, J.H. et al. Nature 388, 903–906 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Berger, J.M., Gamblin, S.J., Harrison, S.C. & Wang, J.C. Nature 379, 225–232 (1996).

    Article  CAS  PubMed  Google Scholar 

  11. McKay, D.B. & Steitz, T.A. Nature 290, 744–749 (1981).

    Article  CAS  PubMed  Google Scholar 

  12. Dong, K.C. & Berger, J.M. Nature 450, 1201–1205 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Rice, P.A., Yang, S., Mizuuchi, K. & Nash, H.A. Cell 87, 1295–1306 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. Pan, X.-S. & Fisher, L.M. Antimicrob. Agents Chemother. 42, 2810–2816 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pan, X.-S., Yague, G. & Fisher, L.M. Antimicrob. Agents Chemother. 45, 3140–3147 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Weigel, L.M., Anderson, G.J., Facklam, R.R. & Tenover, F.C. Antimicrob. Agents Chemother. 45, 3517–3523 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yoshida, H., Bogaki, M., Nakamura, M., Yamanaka, L.M. & Nakamura, S. Antimicrob. Agents Chemother. 35, 1647–1650 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Shen, L.L. et al. Biochemistry 28, 3886–3894 (1989).

    Article  CAS  PubMed  Google Scholar 

  19. Kwok, Y., Zeng, Q. & Hurley, L.H. J. Biol. Chem. 274, 17226–17235 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Humphrey, W., Dalke, A. & Schulten, K. J. Mol. Graph. 14, 33–38 (1996).

    Article  CAS  PubMed  Google Scholar 

  21. Emsley, P. & Cowtan, K. Acta Crystallogr. D Biol. Crystallogr. 60, 2126–2132 (2004).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the IO3 beamline personnel at the DIAMOND synchrotron for their help in collecting native and fixed Pt edge synchrotron data and P. Legrand for his help during MAD data collection at SOLEIL. J. Head and B. Seaton are thanked for providing us with OTCase X-ray diffraction data in space group P32 to test our search algorithms. G. Konrad of Metabion is thanked for her help regarding oligonucleotide synthesis and purification. I.L. was supported by St. George's, University of London. X.-S.P. and R.S. were supported by project grants BBD01882X1 and BBD0144841 (to L.M.F.) from the Biotechnology and Biological Sciences Research Council, UK, D.A.V. by the Guy's and St. Thomas Charitable Trust project grant R050701 and M.K.S. by the UK Medical Research Council.

Author information

Authors and Affiliations

  1. Randall Division of Cell and Molecular Biophysics, King's College London, University of London, London, UK

    Ivan Laponogov, Maninder K Sohi, Dennis A Veselkov & Mark R Sanderson

  2. Division of Basic Medical Sciences, Molecular Genetics Group, Molecular and Metabolic Signalling Centre, St. George's, University of London, London, UK

    Ivan Laponogov, Xiao-Su Pan, Ritica Sawhney & L Mark Fisher

  3. Synchrotron SOLEIL, L'Orme de Merisiers, Saint Aubin-BP48, Gif-sur-Yvette, CEDEX, France

    Andrew W Thompson

  4. Beamline I03, Diamond Light Source, Harwell Science and Innovation Campus, Didcot, Oxfordshire, UK

    Katherine E McAuley

Authors
  1. Ivan Laponogov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maninder K Sohi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dennis A Veselkov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiao-Su Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ritica Sawhney
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andrew W Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Katherine E McAuley
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. L Mark Fisher
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mark R Sanderson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

I.L. crystallized the present complexes, carried out data collection, HKL2000 data processing, structure determination and complete refinement, and wrote the paper; M.K.S. carried out data collection and earlier crystallization of other DNA–topo IV complexes; D.A.V. collected data; X.-S.P. and R.S. performed the biochemical experiments and overexpressed and purified the proteins for crystallization; A.W.T. and K.E.M. performed beamline direction and wavelength monochromation, synchrotron data collection and processing; L.M.F. conceived the experiments and wrote the paper; M.R.S. conceived the experiments, collected data, performed XDS data processing and refinement and wrote the paper.

Corresponding authors

Correspondence to L Mark Fisher or Mark R Sanderson.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3, Supplementary Table 1 and Supplementary Methods (PDF 528 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Laponogov, I., Sohi, M., Veselkov, D. et al. Structural insight into the quinolone–DNA cleavage complex of type IIA topoisomerases. Nat Struct Mol Biol 16, 667–669 (2009). https://doi.org/10.1038/nsmb.1604

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsmb.1604

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing