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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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.).
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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.
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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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