Send to

Choose Destination
ACS Chem Biol. 2015 Jul 17;10(7):1718-28. doi: 10.1021/acschembio.5b00222. Epub 2015 May 1.

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

Author information

†Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2H7.
‡Department of Oncology, University of Alberta, Edmonton, Alberta, Canada T6G 1Z2.
∥Department of Biomedical Genetics, University of Rochester, Rochester, New York 14642, United States.
§Department of Anatomy and Centre for Cancer Research, The University of Hong Kong, Hong Kong, China.


Ubc13 is an E2 ubiquitin conjugating enzyme that functions in nuclear DNA damage signaling and cytoplasmic NF-κB signaling. Here, we present the structures of complexes of Ubc13 with two inhibitors, NSC697923 and BAY 11-7082, which inhibit DNA damage and NF-κB 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-κB 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.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for American Chemical Society Icon for PubMed Central
Loading ...
Support Center