title: 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.
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.
authors.affiliation: Department of Pharmacology, Johns Hopkins School of Medicine, 725 North Wolfe Street, Hunterian Building, Room 516, Baltimore, MD 21205 (USA).
authors.forename: Qing-Li
authors.initials: QL
authors.lastname: He
authors.forename: Denis V
authors.initials: DV
authors.lastname: Titov
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Minjia
authors.initials: M
authors.lastname: Tan
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Ye
authors.forename: Yingming
authors.initials: Y
authors.lastname: Zhao
authors.forename: Daniel
authors.initials: D
authors.lastname: Romo
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
mesh_terms: D003545:Cysteine / Q000737:chemistry*; D004852:Epoxy Compounds / Q000378:metabolism*; D051758:Transcription Factor TFIIH / Q000737:chemistry / Q000378:metabolism*
chemical_list: D004852:Epoxy Compounds; D051758:Transcription Factor TFIIH; D003545:Cysteine
keywords: inhibitors; medicinal chemistry; natural products; target validation; transcription factors