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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
Author(s) -
He QingLi,
Titov Denis V.,
Li Jing,
Tan Minjia,
Ye Zhaohui,
Zhao Yingming,
Romo Daniel,
Liu Jun O.
Publication year - 2015
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201408817
Subject(s) - triptolide , transcription factor ii h , cysteine , chemistry , protein subunit , transcription (linguistics) , sulforaphane , biochemistry , enzyme , dna , nucleotide excision repair , dna damage , apoptosis , linguistics , philosophy , gene
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.