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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Sieber, S.A. & Marahiel, M.A. Chem. Rev. 105, 715–738 (2005).
Walsh, C.T. et al. Curr. Opin. Chem. Biol. 5, 525–534 (2001).
Tanovic, A., Samel, S.A., Essen, L.O. & Marahiel, M.A. Science 321, 659–663 (2008).
Fischbach, M.A. & Walsh, C.T. Chem. Rev. 106, 3468–3496 (2006).
Miller, B.R. & Gulick, A.M. Methods Mol. Biol. 1401, 3–29 (2016).
Bierer, B.E., Holländer, G., Fruman, D. & Burakoff, S.J. Curr. Opin. Immunol. 5, 763–773 (1993).
Chen, S.C., Slavin, M.A. & Sorrell, T.C. Drugs 71, 11–41 (2011).
Bruner, S.D. et al. Structure 10, 301–310 (2002).
Lawen, A. & Zocher, R. J. Biol. Chem. 265, 11355–11360 (1990).
Cacho, R.A., Jiang, W., Chooi, Y.H., Walsh, C.T. & Tang, Y. J. Am. Chem. Soc. 134, 16781–16790 (2012).
Kohli, R.M., Walsh, C.T. & Burkart, M.D. Nature 418, 658–661 (2002).
Gao, X. et al. Nat. Chem. Biol. 8, 823–830 (2012).
Haynes, S.W., Gao, X., Tang, Y. & Walsh, C.T. J. Am. Chem. Soc. 134, 17444–17447 (2012).
Keating, T.A., Marshall, C.G., Walsh, C.T. & Keating, A.E. Nat. Struct. Biol. 9, 522–526 (2002).
Samel, S.A., Schoenafinger, G., Knappe, T.A., Marahiel, M.A. & Essen, L.O. Structure 15, 781–792 (2007).
Bloudoff, K., Rodionov, D. & Schmeing, T.M. J. Mol. Biol. 425, 3137–3150 (2013).
Samel, S.A., Czodrowski, P. & Essen, L.O. Acta Crystallogr. D Biol. Crystallogr. 70, 1442–1452 (2014).
Drake, E.J. et al. Nature 529, 235–238 (2016).
Goldschmidt, L., Cooper, D.R., Derewenda, Z.S. & Eisenberg, D. Protein Sci. 16, 1569–1576 (2007).
Ren, A., Xia, Z.X., Yu, W. & Zhou, J. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 66, 1635–1639 (2010).
Peng, C. et al. Proc. Natl. Acad. Sci. USA 109, 8540–8545 (2012).
Otwinowski, Z. & Minor, W. Methods Enzymol. 276, 307–326 (1997).
Kabsch, W. Acta Crystallogr. D Biol. Crystallogr. 66, 125–132 (2010).
Adams, P.D. et al. Acta Crystallogr. D Biol. Crystallogr. 66, 213–221 (2010).
McCoy, A.J. et al. J. Appl. Crystallogr. 40, 658–674 (2007).
Emsley, P., Lohkamp, B., Scott, W.G. & Cowtan, K. Acta Crystallogr. D Biol. Crystallogr. 66, 486–501 (2010).
Winn, M.D., Murshudov, G.N. & Papiz, M.Z. Methods Enzymol. 374, 300–321 (2003).
Winn, M.D. et al. Acta Crystallogr. D Biol. Crystallogr. 67, 235–242 (2011).
Laskowski, R.A., MacArthur, M.W., Moss, D.S. & Thornton, J.M. J. Appl. Crystallogr. 26, 283–291 (1993).
Chen, V.B. et al. Acta Crystallogr. D Biol. Crystallogr. 66, 12–21 (2010).
Trott, O. & Olson, A.J. J. Comput. Chem. 31, 455–461 (2010).
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
Authors and Affiliations
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
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Results, Supplementary Tables 1–4 and Supplementary Figures 1–11. (PDF 2121 kb)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nchembio.2202
This article is cited by
-
Efficient production of a cyclic dipeptide (cyclo-TA) using heterologous expression system of filamentous fungus Aspergillus oryzae
Microbial Cell Factories (2022)
-
Unexpected assembly machinery for 4(3H)-quinazolinone scaffold synthesis
Nature Communications (2022)
-
AvmM catalyses macrocyclization through dehydration/Michael-type addition in alchivemycin A biosynthesis
Nature Communications (2022)
-
Structural insights into the substrate-bound condensation domains of non-ribosomal peptide synthetase AmbB
Scientific Reports (2022)
-
Structures of a non-ribosomal peptide synthetase condensation domain suggest the basis of substrate selectivity
Nature Communications (2021)