4ONM

Crystal structure of human Mms2/Ubc13 - NSC697923

Summary for 4ONM

• Entry DOI: 10.2210/pdb4onm/pdb
• Related: 4ONL 4ONN
• Descriptor: Ubiquitin-conjugating enzyme E2 variant 2, Ubiquitin-conjugating enzyme E2 N, GLYCEROL, ... (5 entities in total)
• Functional Keywords: e2 ubiquitin conjugating enzyme, e1, e3, ubiquitin, covalent adduct, ligase
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus : P61088
• Total number of polymer chains: 2
• Total formula weight: 35467.57

Authors

Hodge, C.D.,Edwards, R.A.,Glover, J.N.M. (deposition date: 2014-01-28, release date: 2015-05-06, Last modification date: 2024-11-27)

Primary citation

Hodge, C.D.,Edwards, R.A.,Markin, C.J.,McDonald, D.,Pulvino, M.,Huen, M.S.,Zhao, J.,Spyracopoulos, L.,Hendzel, M.J.,Glover, J.N.
Covalent Inhibition of Ubc13 Affects Ubiquitin Signaling and Reveals Active Site Elements Important for Targeting.
Acs Chem.Biol., 10:1718-1728, 2015

PubMed Abstract: 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.

PubMed: 25909880
DOI: 10.1021/acschembio.5b00222

Experimental method

X-RAY DIFFRACTION (1.35 Å)