| Structural highlights
6gzy is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , , |
| Gene: | RNF31, ZIBRA (HUMAN) |
| Activity: | RING-type E3 ubiquitin transferase, with EC number 2.3.2.27 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[RNF31_HUMAN] E3 ubiquitin-protein ligase component of the LUBAC complex which conjugates linear ('M-1'-linked) polyubiquitin chains to substrates and plays a key role in NF-kappa-B activation and regulation of inflammation. LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is involved in activation of the canonical NF-kappa-B and the JNK signaling pathways. Linear ubiquitination mediated by the LUBAC complex interferes with TNF-induced cell death and thereby prevents inflammation. LUBAC is proposed to be recruited to the TNF-R1 signaling complex (TNF-RSC) following polyubiquitination of TNF-RSC components by BIRC2 and/or BIRC3 and to conjugate linear polyubiquitin to IKBKG and possibly other components contributing to the stability of the complex. Binds polyubiquitin of different linkage types.[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
Modification of proteins with polyubiquitin chains is a key regulatory mechanism to control cellular behavior and altera-tions in the ubiquitin system are linked to many diseases. Linear (M1-linked) polyubiquitin chains play pivotal roles in several cellular signalling pathways mediating immune and inflammatory responses and apoptotic cell death. These chains are formed by the linear ubiquitin chain assembly complex (LUBAC), a multi-protein E3 ligase that consists of 3 subunits, HOIP, HOIL-1L and SHARPIN. Herein, we describe the discovery of inhibitors targeting the active site cysteine of the catalytic subunit HOIP using fragment-based covalent ligand screening. We report the synthesis of a diverse library of electrophilic fragments and demonstrate an integrated use of protein LC-MS, biochemical ubiquitination assays, chemi-cal synthesis and protein crystallography to enable the first structure-based development of covalent inhibitors for an RBR E3 ligase. Furthermore, using cell-based assays and chemoproteomics we demonstrate that these compounds effec-tively penetrate mammalian cells to label and inhibit HOIP and NF-kappaB activation, making them suitable hits for the devel-opment of selective probes to study LUBAC biology. Our results illustrate the power of fragment-based covalent ligand screening to discover lead compounds for challenging targets, which holds promise to be a general approach for the de-velopment of cell-permeable inhibitors of thioester-forming E3 ubiquitin ligases.
Fragment-based covalent ligand screening enables rapid discovery of inhibitors for the RBR E3 ubiquitin ligase HOIP.,Johansson H, Tsai YI, Fantom K, Chung CW, Kumper S, Martino L, Thomas DA, Eberl HC, Muelbaier M, House D, Rittinger K J Am Chem Soc. 2019 Jan 18. doi: 10.1021/jacs.8b13193. PMID:30657686[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kirisako T, Kamei K, Murata S, Kato M, Fukumoto H, Kanie M, Sano S, Tokunaga F, Tanaka K, Iwai K. A ubiquitin ligase complex assembles linear polyubiquitin chains. EMBO J. 2006 Oct 18;25(20):4877-87. Epub 2006 Sep 28. PMID:17006537 doi:10.1038/sj.emboj.7601360
- ↑ Haas TL, Emmerich CH, Gerlach B, Schmukle AC, Cordier SM, Rieser E, Feltham R, Vince J, Warnken U, Wenger T, Koschny R, Komander D, Silke J, Walczak H. Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol Cell. 2009 Dec 11;36(5):831-44. doi: 10.1016/j.molcel.2009.10.013. PMID:20005846 doi:10.1016/j.molcel.2009.10.013
- ↑ Tokunaga F, Sakata S, Saeki Y, Satomi Y, Kirisako T, Kamei K, Nakagawa T, Kato M, Murata S, Yamaoka S, Yamamoto M, Akira S, Takao T, Tanaka K, Iwai K. Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation. Nat Cell Biol. 2009 Feb;11(2):123-32. doi: 10.1038/ncb1821. Epub 2009 Jan 11. PMID:19136968 doi:10.1038/ncb1821
- ↑ Gerlach B, Cordier SM, Schmukle AC, Emmerich CH, Rieser E, Haas TL, Webb AI, Rickard JA, Anderton H, Wong WW, Nachbur U, Gangoda L, Warnken U, Purcell AW, Silke J, Walczak H. Linear ubiquitination prevents inflammation and regulates immune signalling. Nature. 2011 Mar 31;471(7340):591-6. doi: 10.1038/nature09816. PMID:21455173 doi:10.1038/nature09816
- ↑ Tokunaga F, Nakagawa T, Nakahara M, Saeki Y, Taniguchi M, Sakata S, Tanaka K, Nakano H, Iwai K. SHARPIN is a component of the NF-kappaB-activating linear ubiquitin chain assembly complex. Nature. 2011 Mar 31;471(7340):633-6. doi: 10.1038/nature09815. PMID:21455180 doi:10.1038/nature09815
- ↑ Ikeda F, Deribe YL, Skanland SS, Stieglitz B, Grabbe C, Franz-Wachtel M, van Wijk SJ, Goswami P, Nagy V, Terzic J, Tokunaga F, Androulidaki A, Nakagawa T, Pasparakis M, Iwai K, Sundberg JP, Schaefer L, Rittinger K, Macek B, Dikic I. SHARPIN forms a linear ubiquitin ligase complex regulating NF-kappaB activity and apoptosis. Nature. 2011 Mar 31;471(7340):637-41. doi: 10.1038/nature09814. PMID:21455181 doi:10.1038/nature09814
- ↑ Smit JJ, Monteferrario D, Noordermeer SM, van Dijk WJ, van der Reijden BA, Sixma TK. The E3 ligase HOIP specifies linear ubiquitin chain assembly through its RING-IBR-RING domain and the unique LDD extension. EMBO J. 2012 Oct 3;31(19):3833-44. doi: 10.1038/emboj.2012.217. Epub 2012 Aug 3. PMID:22863777 doi:10.1038/emboj.2012.217
- ↑ Johansson H, Tsai YI, Fantom K, Chung CW, Kumper S, Martino L, Thomas DA, Eberl HC, Muelbaier M, House D, Rittinger K. Fragment-based covalent ligand screening enables rapid discovery of inhibitors for the RBR E3 ubiquitin ligase HOIP. J Am Chem Soc. 2019 Jan 18. doi: 10.1021/jacs.8b13193. PMID:30657686 doi:http://dx.doi.org/10.1021/jacs.8b13193
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