6gzy
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==HOIP-fragment5 complex== | |
| + | <StructureSection load='6gzy' size='340' side='right' caption='[[6gzy]], [[Resolution|resolution]] 2.15Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6gzy]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GZY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GZY FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FHH:methyl+4-[(2-oxidanylidene-1,5,6,7-tetrahydrocyclopenta[b]pyridin-3-yl)carbonylamino]butanoate'>FHH</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/RING-type_E3_ubiquitin_transferase RING-type E3 ubiquitin transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.2.27 2.3.2.27] </span></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6gzy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6gzy OCA], [http://pdbe.org/6gzy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6gzy RCSB], [http://www.ebi.ac.uk/pdbsum/6gzy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6gzy ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/RNF31_HUMAN 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.<ref>PMID:17006537</ref> <ref>PMID:20005846</ref> <ref>PMID:19136968</ref> <ref>PMID:21455173</ref> <ref>PMID:21455180</ref> <ref>PMID:21455181</ref> <ref>PMID:22863777</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == 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<ref>PMID:30657686</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | <div class="pdbe-citations 6gzy" style="background-color:#fffaf0;"></div> | |
| - | [[Category: | + | == References == |
| - | [[Category: Chung, C | + | <references/> |
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: RING-type E3 ubiquitin transferase]] | ||
| + | [[Category: Chung, C W]] | ||
[[Category: Fantom, K]] | [[Category: Fantom, K]] | ||
[[Category: House, D]] | [[Category: House, D]] | ||
[[Category: Johansson, H]] | [[Category: Johansson, H]] | ||
[[Category: Martino, L]] | [[Category: Martino, L]] | ||
| + | [[Category: Rittinger, K]] | ||
| + | [[Category: Tsai, Y C.I]] | ||
| + | [[Category: E3]] | ||
| + | [[Category: Inhibitor complex]] | ||
| + | [[Category: Ligase]] | ||
| + | [[Category: Ubiquitin ligase]] | ||
Revision as of 08:26, 30 January 2019
HOIP-fragment5 complex
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