Article | Published:

XPB, a subunit of TFIIH, is a target of the natural product triptolide

Nature Chemical Biology volume 7, pages 182188 (2011) | Download Citation

Abstract

Triptolide (1) is a structurally unique diterpene triepoxide isolated from a traditional Chinese medicinal plant with anti-inflammatory, immunosuppressive, contraceptive and antitumor activities. Its molecular mechanism of action, however, has remained largely elusive to date. We report that triptolide covalently binds to human XPB (also known as ERCC3), a subunit of the transcription factor TFIIH, and inhibits its DNA-dependent ATPase activity, which leads to the inhibition of RNA polymerase II–mediated transcription and likely nucleotide excision repair. The identification of XPB as the target of triptolide accounts for the majority of the known biological activities of triptolide. These findings also suggest that triptolide can serve as a new molecular probe for studying transcription and, potentially, as a new type of anticancer agent through inhibition of the ATPase activity of XPB.

  • Compound C20H24O6

    Triptolide

  • Compound C20H24O6

    14-epi-Triptolide

  • Compound C20H24O7

    5α-Hydroxytriptolide

  • Compound C20H22O6

    Triptonide

  • Compound C20H22O7

    5α-Hydroxytriptonide

  • Compound C24H26N2O6S

    14-(1H-Imidazole-1-carbothioyl)triptolide

  • Compound C20H23FO5

    14-Deoxy-14α-fluorotriptolide

  • Compound C21H24O6

    (14S)-Triptolide-14-spiro-1'-oxirane

  • Compound C21H24O7

    (14S)-5α-Hydroxytriptolide-14-spiro-1'-oxirane

  • Compound C21H25ClO6

    (14S)-12-Deoxy-12β-chloro-13α-hydroxytriptolide-14-spiro-1'-oxirane

  • Compound C20H26O6

    7-Deoxy-8β-hydroxytriptolide

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Acknowledgements

This work was supported by discretionary funds (J.O.L.). We are grateful to A. Gnatt (University of Maryland) for a kind gift of purified RNAPII and B. Sollner-Webb (Johns Hopkins University) for plasmids. We thank D. Yang for earlier support of this project. We thank P. Cole, J. Corden, J. Stivers and members of the Liu lab for helpful suggestions.

Author information

Affiliations

  1. Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Denis V Titov
    • , Qing-Li He
    • , Shridhar Bhat
    • , Woon-Kai Low
    • , Yongjun Dang
    •  & Jun O Liu
  2. Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado, USA.

    • Benjamin Gilman
    • , Jennifer F Kugel
    •  & James A Goodrich
  3. Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.

    • Michael Smeaton
    •  & Paul S Miller
  4. Charles A. Dana Research Institute for Scientists Emeriti, Drew University, Madison, New Jersey, USA.

    • Arnold L Demain
  5. Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Jun O Liu
  6. Present: Department of Pharmaceutical Sciences, College of Pharmacy, St. John's University, Queens, New York, USA (W.-K.L.).

    • Woon-Kai Low

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Contributions

D.V.T., J.A.G., P.S.M. and J.O.L. designed the experiments. D.V.T., B.G., Q.-L.H., S.B., W.-K.L. and M.S. performed the experiments. W.-K.L., A.L.D., P.S.M., J.F.K., Y.D. and J.A.G. contributed reagents. D.V.T. and J.O.L. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jun O Liu.

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DOI

https://doi.org/10.1038/nchembio.522

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