title: XPB, a subunit of TFIIH, is a target of the natural product triptolide.
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.
authors.affiliation: Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Denis V
authors.initials: DV
authors.lastname: Titov
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gilman
authors.forename: Qing-Li
authors.initials: QL
authors.lastname: He
authors.forename: Shridhar
authors.initials: S
authors.lastname: Bhat
authors.forename: Woon-Kai
authors.initials: WK
authors.lastname: Low
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Dang
authors.forename: Michael
authors.initials: M
authors.lastname: Smeaton
authors.forename: Arnold L
authors.initials: AL
authors.lastname: Demain
authors.forename: Paul S
authors.initials: PS
authors.lastname: Miller
authors.forename: Jennifer F
authors.initials: JF
authors.lastname: Kugel
authors.forename: James A
authors.initials: JA
authors.lastname: Goodrich
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004265:DNA Helicases / Q000737:chemistry / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D004852:Epoxy Compounds / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D010616:Phenanthrenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D011485:Protein Binding; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D051758:Transcription Factor TFIIH / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001688:Biological Products; D004268:DNA-Binding Proteins; D004224:Diterpenes; D004365:Drugs, Chinese Herbal; D004852:Epoxy Compounds; D010616:Phenanthrenes; D021122:Protein Subunits; C072022:XPBC-ERCC-3 protein; D051758:Transcription Factor TFIIH; C001899:triptolide; D012319:RNA Polymerase II; D000251:Adenosine Triphosphatases; D004265:DNA Helicases