6KC6

HOIP-HOIPIN8 complex

Summary for 6KC6

• Entry DOI: 10.2210/pdb6kc6/pdb
• Descriptor: E3 ubiquitin-protein ligase RNF31, ZINC ION, 2-[3-[2,6-bis(fluoranyl)-4-(1~{H}-pyrazol-4-yl)phenyl]-3-oxidanylidene-propyl]-4-(1-methylpyrazol-4-yl)benzoic acid, ... (6 entities in total)
• Functional Keywords: ubiquitin, e3, inhibitor complex, ligase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 6
• Total formula weight: 157642.32

Authors

Sato, Y.,Fukai, S. (deposition date: 2019-06-27, release date: 2020-04-15, Last modification date: 2023-11-22)

Primary citation

Oikawa, D.,Sato, Y.,Ohtake, F.,Komakura, K.,Hanada, K.,Sugawara, K.,Terawaki, S.,Mizukami, Y.,Phuong, H.T.,Iio, K.,Obika, S.,Fukushi, M.,Irie, T.,Tsuruta, D.,Sakamoto, S.,Tanaka, K.,Saeki, Y.,Fukai, S.,Tokunaga, F.
Molecular bases for HOIPINs-mediated inhibition of LUBAC and innate immune responses.
Commun Biol, 3:163-163, 2020

PubMed Abstract: The NF-κB and interferon antiviral signaling pathways play pivotal roles in inflammatory and innate immune responses. The LUBAC ubiquitin ligase complex, composed of the HOIP, HOIL-1L, and SHARPIN subunits, activates the canonical NF-κB pathway through Met1-linked linear ubiquitination. We identified small-molecule chemical inhibitors of LUBAC, HOIPIN-1 and HOIPIN-8. Here we show that HOIPINs down-regulate not only the proinflammatory cytokine-induced canonical NF-κB pathway, but also various pathogen-associated molecular pattern-induced antiviral pathways. Structural analyses indicated that HOIPINs inhibit the RING-HECT-hybrid reaction in HOIP by modifying the active Cys885, and residues in the C-terminal LDD domain, such as Arg935 and Asp936, facilitate the binding of HOIPINs to LUBAC. HOIPINs effectively induce cell death in activated B cell-like diffuse large B cell lymphoma cells, and alleviate imiquimod-induced psoriasis in model mice. These results reveal the molecular and cellular bases of LUBAC inhibition by HOIPINs, and demonstrate their potential therapeutic uses.

PubMed: 32246052
DOI: 10.1038/s42003-020-0882-8

Experimental method

X-RAY DIFFRACTION (2.123 Å)