5O6T

BIRC4 RING in complex with dimeric ubiquitin variant

Summary for 5O6T

• Entry DOI: 10.2210/pdb5o6t/pdb
• Descriptor: E3 ubiquitin-protein ligase XIAP, Polyubiquitin-B, ZINC ION, ... (5 entities in total)
• Functional Keywords: e3 ring ligase, ubiquitin variant, ligase
• Biological source: Homo sapiens (Human); More
• Cellular location: Cytoplasm: P98170; Ubiquitin: Cytoplasm : P0CG47
• Total number of polymer chains: 4
• Total formula weight: 33606.43

Authors

Gabrielsen, M.,Buetow, L.,Huang, D.T. (deposition date: 2017-06-07, release date: 2017-11-01, Last modification date: 2024-01-17)

Primary citation

Gabrielsen, M.,Buetow, L.,Nakasone, M.A.,Ahmed, S.F.,Sibbet, G.J.,Smith, B.O.,Zhang, W.,Sidhu, S.S.,Huang, D.T.
A General Strategy for Discovery of Inhibitors and Activators of RING and U-box E3 Ligases with Ubiquitin Variants.
Mol. Cell, 68:456-470.e10, 2017

PubMed 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.

PubMed: 29053960
DOI: 10.1016/j.molcel.2017.09.027

Experimental method

X-RAY DIFFRACTION (1.57 Å)