9QUG

Structure of a UBC-Ubiquitin conjugate

Summary for 9QUG

• Entry DOI: 10.2210/pdb9qug/pdb
• Descriptor: Polyubiquitin-B, (E3-independent) E2 ubiquitin-conjugating enzyme, GLYCEROL, ... (5 entities in total)
• Functional Keywords: e2/e3 enzyme ubc domain conjugated to ubiquitin, ligase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 52635.48

Authors

Kordic, D.,Williams, T.L.,Luiza Deszcz, L.,Ehrmann, J.,Arnese, R.,Meinhart, A.,Clausen, T. (deposition date: 2025-04-10, release date: 2026-01-21)

Primary citation

Kordic, D.,Williams, T.L.,Deszcz, L.,Ehrmann, J.F.,Arnese, R.,Schleiffer, A.,Clausen, T.,Meinhart, A.
Structural basis for substrate recruitment and catalytic ubiquitin transfer by the E2/E3 hybrid enzyme UBE2O.
J.Biol.Chem., 302:111073-111073, 2025

PubMed Abstract: UBE2O is a promiscuous ubiquitin ligase involved in cellular quality control pathways. Along with BIRC6, UBE2O is one of only two E2 enzymes that can ubiquitinate substrates in an E3-independent manner. The E2/E3 hybrid targets and multi-monoubiquitinates a multitude of orphan proteins; however, the mechanisms underlying substrate specificity and ubiquitin transfer remain poorly understood. By combining structural and biochemical approaches, we show that substrate binding by UBE2O occurs through a conserved acidic pocket formed by the N-terminal SH3-like domains and that this platform allows the recruitment of a broad range of proteins. Furthermore, we identified specific residues in the catalytic UBC domain that position ubiquitin in a closed state, confirming its confirmation, and priming it for nucleophilic attack by the incoming substrate. Importantly, the activated E2∼Ub conjugate is protected by a tryptophan residue, avoiding premature hydrolysis. By incorporating these findings into the UBC domain of BIRC6 our data provide the molecular basis of how specialized E2/E3 hybrid proteins function as potent ubiquitination enzymes reminiscent of the catalytic principle of RING E3 ligases.

PubMed: 41419192
DOI: 10.1016/j.jbc.2025.111073

Experimental method

X-RAY DIFFRACTION (1.8 Å)