PDBsum entry 5o6t

Ligase

PDB id: 5o6t

Contents

Protein chains

64 a.a.

75 a.a.

Ligands

EDO ×2

Metals

_ZN ×4

Waters ×218

References listed in PDB file

Key reference

• Title: A general strategy for discovery of inhibitors and activators of ring and u-Box e3 ligases with ubiquitin variants.
• Authors: M.Gabrielsen, L.Buetow, M.A.Nakasone, S.F.Ahmed, G.J.Sibbet, B.O.Smith, W.Zhang, S.S.Sidhu, D.T.Huang.
• Ref.: Mol Cell, 2017, 68, 456.
• PubMed id: 29053960

Abstract

RING and U-box E3 ubiquitin ligases regulate diverse eukaryotic processes and have been implicated in numerous diseases, but targeting these enzymes remains a major challenge. We report the development of three ubiquitin variants (UbVs), each binding selectively to the RING or U-box domain of a distinct E3 ligase: monomeric UBE4B, phosphorylated active CBL, or dimeric XIAP. Structural and biochemical analyses revealed that UbVs specifically inhibited the activity of UBE4B or phosphorylated CBL by blocking the E2∼Ub binding site. Surprisingly, the UbV selective for dimeric XIAP formed a dimer to stimulate E3 activity by stabilizing the closed E2∼Ub conformation. We further verified the inhibitory and stimulatory functions of UbVs in cells. Our work provides a general strategy to inhibit or activate RING/U-box E3 ligases and provides a resource for the research community to modulate these enzymes.