6KC5
HOIP-HOIPIN1 complex
Summary for 6KC5
| Entry DOI | 10.2210/pdb6kc5/pdb |
| Descriptor | E3 ubiquitin-protein ligase RNF31, ZINC ION, 2-[3-(2-methoxyphenyl)-3-oxidanylidene-propyl]benzoic acid, ... (6 entities in total) |
| Functional Keywords | ubiquitin, e3, inhibitor complex, ligase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 26521.63 |
| Authors | |
| 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 Cited by 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: 32246052DOI: 10.1038/s42003-020-0882-8 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.543 Å) |
Structure validation
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