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Structural basis of nonribosomal peptide macrocyclization in fungi

Nature Chemical Biology volume 12, pages 1001–1003 (2016)Cite this article

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Abstract

Nonribosomal peptide synthetases (NRPSs) in fungi biosynthesize important pharmaceutical compounds, including penicillin, cyclosporine and echinocandin. To understand the fungal strategy of forging the macrocyclic peptide linkage, we determined the crystal structures of the terminal condensation-like (CT) domain and the holo thiolation (T)-CT complex of Penicillium aethiopicum TqaA. The first, to our knowledge, structural depiction of the terminal module in a fungal NRPS provides a molecular blueprint for generating new macrocyclic peptide natural products.

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Figure 1: The reaction catalyzed by and overall structure of the CT domain.
Figure 2: The crystal structure of the T-CT complex in the holo form.

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References

  1. Sieber, S.A. & Marahiel, M.A. Chem. Rev. 105, 715–738 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Walsh, C.T. et al. Curr. Opin. Chem. Biol. 5, 525–534 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Tanovic, A., Samel, S.A., Essen, L.O. & Marahiel, M.A. Science 321, 659–663 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Fischbach, M.A. & Walsh, C.T. Chem. Rev. 106, 3468–3496 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Miller, B.R. & Gulick, A.M. Methods Mol. Biol. 1401, 3–29 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bierer, B.E., Holländer, G., Fruman, D. & Burakoff, S.J. Curr. Opin. Immunol. 5, 763–773 (1993).

    Article  CAS  PubMed  Google Scholar 

  7. Chen, S.C., Slavin, M.A. & Sorrell, T.C. Drugs 71, 11–41 (2011).

    Article  PubMed  Google Scholar 

  8. Bruner, S.D. et al. Structure 10, 301–310 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Lawen, A. & Zocher, R. J. Biol. Chem. 265, 11355–11360 (1990).

    CAS  PubMed  Google Scholar 

  10. Cacho, R.A., Jiang, W., Chooi, Y.H., Walsh, C.T. & Tang, Y. J. Am. Chem. Soc. 134, 16781–16790 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kohli, R.M., Walsh, C.T. & Burkart, M.D. Nature 418, 658–661 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Gao, X. et al. Nat. Chem. Biol. 8, 823–830 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Haynes, S.W., Gao, X., Tang, Y. & Walsh, C.T. J. Am. Chem. Soc. 134, 17444–17447 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Keating, T.A., Marshall, C.G., Walsh, C.T. & Keating, A.E. Nat. Struct. Biol. 9, 522–526 (2002).

    CAS  PubMed  Google Scholar 

  15. Samel, S.A., Schoenafinger, G., Knappe, T.A., Marahiel, M.A. & Essen, L.O. Structure 15, 781–792 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Bloudoff, K., Rodionov, D. & Schmeing, T.M. J. Mol. Biol. 425, 3137–3150 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Samel, S.A., Czodrowski, P. & Essen, L.O. Acta Crystallogr. D Biol. Crystallogr. 70, 1442–1452 (2014).

    Article  CAS  PubMed  Google Scholar 

  18. Drake, E.J. et al. Nature 529, 235–238 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Goldschmidt, L., Cooper, D.R., Derewenda, Z.S. & Eisenberg, D. Protein Sci. 16, 1569–1576 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ren, A., Xia, Z.X., Yu, W. & Zhou, J. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 66, 1635–1639 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Peng, C. et al. Proc. Natl. Acad. Sci. USA 109, 8540–8545 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Otwinowski, Z. & Minor, W. Methods Enzymol. 276, 307–326 (1997).

    Article  CAS  PubMed  Google Scholar 

  23. Kabsch, W. Acta Crystallogr. D Biol. Crystallogr. 66, 125–132 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Adams, P.D. et al. Acta Crystallogr. D Biol. Crystallogr. 66, 213–221 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. McCoy, A.J. et al. J. Appl. Crystallogr. 40, 658–674 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Emsley, P., Lohkamp, B., Scott, W.G. & Cowtan, K. Acta Crystallogr. D Biol. Crystallogr. 66, 486–501 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Winn, M.D., Murshudov, G.N. & Papiz, M.Z. Methods Enzymol. 374, 300–321 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Winn, M.D. et al. Acta Crystallogr. D Biol. Crystallogr. 67, 235–242 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Laskowski, R.A., MacArthur, M.W., Moss, D.S. & Thornton, J.M. J. Appl. Crystallogr. 26, 283–291 (1993).

    Article  CAS  Google Scholar 

  30. Chen, V.B. et al. Acta Crystallogr. D Biol. Crystallogr. 66, 12–21 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Trott, O. & Olson, A.J. J. Comput. Chem. 31, 455–461 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the staff at beamline BL17U1 of the Shanghai Synchrotron Radiation Facility (China), beamline BL5a of the Photon Factory (Japan), and beamlines BL19U1 and 19U2 of National Center for Protein Science Shanghai (China) for access and help with data collection. This work was supported by grants from the Science and Technology Commission of Shanghai Municipality (15JC1400403 to J.Z.), the Chinese Ministry of Science and Technology (2013CB910200 to C.T.), the National Natural Science Foundation of China (31470187 to J. Z.), US National Institutes of Health (1DP1GM106413 and 1R35GM118056 to Y.T.), and the Open Fund from the State Key Laboratory of Bioreactor Engineering and the State Key Laboratory of Microbial Metabolism at Shanghai Jiao Tong University (to J. Z.).

Author information

Author notes

  1. Ralph A Cacho

    Present address: Present address: Institute of Protein Design, Department of Biochemistry, University of Washington, Molecular Engineering and Sciences, Seattle, Washington, USA.,

  2. Nicholas Liu and Ralph A Cacho: These authors contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

    Jinru Zhang & Jiahai Zhou

  2. Department of Chemical and Biomolecular Engineering, Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California, USA

    Nicholas Liu, Ralph A Cacho & Yi Tang

  3. CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, China

    Zhou Gong & Chun Tang

  4. Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China

    Zhu Liu & Chun Tang

  5. National Center for Protein Science Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    Wenming Qin

  6. Shanghai Collaborative Innovation Center for Biomanufacturing Technology, Shanghai, China

    Jiahai Zhou

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  1. Jinru Zhang
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Contributions

J. Zhang purified and crystallized protein samples and solved the X-ray structures; N.L. and R.A.C. measured the mutant activity assays in vivo and performed docking experiments; Z.G. and Z.L. prepared samples; W.Q. collected the X-ray diffraction data; and J. Zhang, N.L., R.A.C., C.T., Y.T. and J. Zhou designed the experimental approach, analyzed data and wrote the manuscript.

Corresponding authors

Correspondence to Yi Tang or Jiahai Zhou.

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The authors declare no competing financial interests.

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Supplementary Results, Supplementary Tables 1–4 and Supplementary Figures 1–11. (PDF 2121 kb)

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Zhang, J., Liu, N., Cacho, R. et al. Structural basis of nonribosomal peptide macrocyclization in fungi. Nat Chem Biol 12, 1001–1003 (2016). https://doi.org/10.1038/nchembio.2202

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  • DOI: https://doi.org/10.1038/nchembio.2202

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