Covalent Inhibition of Ubc13 Affects Ubiquitin Signaling and Reveals Active Site Elements Important for Targeting

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• 作者：Curtis D. Hodge ; Ross A. Edwards ; Craig J. Markin ; Darin McDonald ; Mary Pulvino ; Michael S. Y. Huen ; Jiyong Zhao ; Leo Spyracopoulos ; Michael J. Hendzel ; J. N. Mark Glover
• 刊名：ACS Chemical Biology
• 出版年：2015
• 出版时间：July 17, 2015
• 年：2015
• 卷：10
• 期：7
• 页码：1718-1728
• 全文大小：624K
• ISSN：1554-8937

文摘

Ubc13 is an E2 ubiquitin conjugating enzyme that functions in nuclear DNA damage signaling and cytoplasmic NF-魏B signaling. Here, we present the structures of complexes of Ubc13 with two inhibitors, NSC697923 and BAY 11-7082, which inhibit DNA damage and NF-魏B signaling in human cells. NSC697923 and BAY 11-7082 both inhibit Ubc13 by covalent adduct formation through a Michael addition at the Ubc13 active site cysteine. The resulting adducts of both compounds exploit a binding groove unique to Ubc13. We developed a Ubc13 mutant which resists NSC697923 inhibition and, using this mutant, we show that the inhibition of cellular DNA damage and NF-魏B signaling by NSC697923 is largely due to specific Ubc13 inhibition. We propose that unique structural features near the Ubc13 active site could provide a basis for the rational development and design of specific Ubc13 inhibitors.