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ATP-directed capture of bioactive herbal-based medicine on human tRNA synthetase

Nature volume 494, pages 121–124 (2013)Cite this article

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Abstract

Febrifugine is the active component of the Chinese herb Chang Shan (Dichroa febrifuga Lour.)1,2, which has been used for treating malaria-induced fever for about 2,000 years. Halofuginone (HF), the halogenated derivative of febrifugine, has been tested in clinical trials for potential therapeutic applications in cancer and fibrotic disease3,4,5,6. Recently, HF was reported to inhibit TH17 cell differentiation by activating the amino acid response pathway7, through inhibiting human prolyl-transfer RNA synthetase (ProRS) to cause intracellular accumulation of uncharged tRNA8,9. Curiously, inhibition requires the presence of unhydrolysed ATP. Here we report an unusual 2.0 Å structure showing that ATP directly locks onto and orients two parts of HF onto human ProRS, so that one part of HF mimics bound proline and the other mimics the 3′ end of bound tRNA. Thus, HF is a new type of ATP-dependent inhibitor that simultaneously occupies two different substrate binding sites on ProRS. Moreover, our structure indicates a possible similar mechanism of action for febrifugine in malaria treatment. Finally, the elucidation here of a two-site modular targeting activity of HF raises the possibility that substrate-directed capture of similar inhibitors might be a general mechanism that could be applied to other synthetases.

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Figure 1: Structure of human ProRS with bound ligands.
Figure 2: Mechanistic basis for ATP-dependent inhibition of ProRS by halofuginone.
Figure 3: HF interacts with both the site for amino acid activation and the site for docking the 3′-end of tRNA.
Figure 4: Febrifugine blocks ProRS.

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Protein Data Bank

Data deposits

Atomic coordinates and structure factors for the reported crystal structure have been deposited in the Protein Data Bank under accession code 4HVC.

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Acknowledgements

We thank K. Musier-Forsyth for providing the ProRS gene plasmid and Pro-SA, staff at beamline 7-1 of Stanford Synchrotron Radiation Lightsource for assistance in X-ray diffraction data collection, and M. Guo for comments. This work was supported by National Institutes of Health grants GM15539, GM23562 and GM88278 and by a fellowship from the National Foundation for Cancer Research.

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Authors and Affiliations

  1. Department of Molecular Biology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA,

    Huihao Zhou, Litao Sun, Xiang-Lei Yang & Paul Schimmel

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  1. Huihao Zhou
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  2. Litao Sun
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Contributions

H.Z., L.S., X.-L.Y. and P.S. designed the experiments. H.Z. and L.S. performed the experiments and all authors analysed the data. All authors discussed the results and H.Z. and P.S. wrote the manuscript.

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Correspondence to Paul Schimmel.

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The authors declare no competing financial interests.

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Zhou, H., Sun, L., Yang, XL. et al. ATP-directed capture of bioactive herbal-based medicine on human tRNA synthetase. Nature 494, 121–124 (2013). https://doi.org/10.1038/nature11774

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