Covalent modification of a cysteine residue in the XPB subunit of the general transcription factor TFIIH through single epoxide cleavage of the transcription inhibitor triptolide

Qing Li He, Denis V. Titov, Jing Li, Minjia Tan, Zhaohui Ye, Yingming Zhao, Daniel Romo, Jun O. Liu

Research output: Contribution to journalArticlepeer-review

Abstract

Triptolide is a key component of the traditional Chinese medicinal plant Thunder God Vine and has potent anticancer and immunosuppressive activities. It is an irreversible inhibitor of eukaryotic transcription through covalent modification of XPB, a subunit of the general transcription factor TFIIH. Cys342 of XPB was identified as the residue that undergoes covalent modification by the 12,13-epoxide group of triptolide. Mutation of Cys342 of XPB to threonine conferred resistance to triptolide on the mutant protein. Replacement of the endogenous wild-type XPB with the Cys342Thr mutant in a HEK293T cell line rendered it completely resistant to triptolide, thus validating XPB as the physiologically relevant target of triptolide. Together, these results deepen our understanding of the interaction between triptolide and XPB and have implications for the future development of new analogues of triptolide as leads for anticancer and immunosuppressive drugs.

Original languageEnglish (US)
Pages (from-to)1859-1863
Number of pages5
JournalAngewandte Chemie - International Edition
Volume54
Issue number6
DOIs
StatePublished - Feb 9 2015

Keywords

  • ,target validation
  • Inhibitors
  • Medicinal chemistry
  • Natural products
  • Transcription factors

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

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