5c7m

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'''Unreleased structure'''
 
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The entry 5c7m is ON HOLD
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==CRYSTAL STRUCTURE OF E3 LIGASE ITCH WITH A UB VARIANT==
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<StructureSection load='5c7m' size='340' side='right'caption='[[5c7m]], [[Resolution|resolution]] 3.03&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[5c7m]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5C7M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5C7M FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.03&#8491;</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5c7m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5c7m OCA], [https://pdbe.org/5c7m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5c7m RCSB], [https://www.ebi.ac.uk/pdbsum/5c7m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5c7m ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/ITCH_HUMAN ITCH_HUMAN] Defects in ITCH are the cause of syndromic multisystem autoimmune disease (SMAD) [MIM:[https://omim.org/entry/613385 613385]. SMAD is characterized by organomegaly, failure to thrive, developmental delay, dysmorphic features and autoimmune inflammatory cell infiltration of the lungs, liver and gut.<ref>PMID:20170897</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/ITCH_HUMAN ITCH_HUMAN] Acts as an E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. It catalyzes 'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation. It is involved in the control of inflammatory signaling pathways. Is an essential component of a ubiquitin-editing protein complex, comprising also TNFAIP3, TAX1BP1 and RNF11, that ensures the transient nature of inflammatory signaling pathways. Promotes the association of the complex after TNF stimulation. Once the complex is formed, TNFAIP3 deubiquitinates 'Lys-63' polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains. This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NFKB1. Ubiquitinates RIPK2 by 'Lys-63'-linked conjugation and influences NOD2-dependent signal transduction pathways. Regulates the transcriptional activity of several transcription factors, and probably plays an important role in the regulation of immune response. Ubiquitinates NFE2 by 'Lys-63' linkages and is implicated in the control of the development of hematopoietic lineages. Critical regulator of T-helper (TH2) cytokine development through its ability to induce JUNB ubiquitination and degradation (By similarity). Ubiquitinates SNX9. Ubiquitinates CXCR4 and HGS/HRS and regulates sorting of CXCR4 to the degradative pathway. It is involved in the negative regulation of MAVS-dependent cellular antiviral responses. Ubiquitinates MAVS through 'Lys-48'-linked conjugation resulting in MAVS proteasomal degradation. Involved in the regulation of apoptosis and reactive oxygen species levels through the ubiquitination and proteasomal degradation of TXNIP. Mediates the antiapoptotic activity of epidermal growth factor through the ubiquitination and proteasomal degradation of p15 BID. Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked polyubiquitination.<ref>PMID:14602072</ref> <ref>PMID:17028573</ref> <ref>PMID:16387660</ref> <ref>PMID:18718448</ref> <ref>PMID:18718449</ref> <ref>PMID:18628966</ref> <ref>PMID:19592251</ref> <ref>PMID:19131965</ref> <ref>PMID:19881509</ref> <ref>PMID:20392206</ref> <ref>PMID:20068034</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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HECT-family E3 ligases ubiquitinate protein substrates to control virtually every eukaryotic process and are misregulated in numerous diseases. Nonetheless, understanding of HECT E3s is limited by a paucity of selective and potent modulators. To overcome this challenge, we systematically developed ubiquitin variants (UbVs) that inhibit or activate HECT E3s. Structural analysis of 6 HECT-UbV complexes revealed UbV inhibitors hijacking the E2-binding site and activators occupying a ubiquitin-binding exosite. Furthermore, UbVs unearthed distinct regulation mechanisms among NEDD4 subfamily HECTs and proved useful for modulating therapeutically relevant targets of HECT E3s in cells and intestinal organoids, and in a genetic screen that identified a role for NEDD4L in regulating cell migration. Our work demonstrates versatility of UbVs for modulating activity across an E3 family, defines mechanisms and provides a toolkit for probing functions of HECT E3s, and establishes a general strategy for systematic development of modulators targeting families of signaling proteins.
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Authors: Walker, J.R., Hu, J., Dong, A., Wernimont, A., Zhang, W., Sidhu, S., Bountra, C., Edwards, A.M., Arrowsmith, C.H., Tong, Y., Structural Genomics Consortium (SGC)
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System-Wide Modulation of HECT E3 Ligases with Selective Ubiquitin Variant Probes.,Zhang W, Wu KP, Sartori MA, Kamadurai HB, Ordureau A, Jiang C, Mercredi PY, Murchie R, Hu J, Persaud A, Mukherjee M, Li N, Doye A, Walker JR, Sheng Y, Hao Z, Li Y, Brown KR, Lemichez E, Chen J, Tong Y, Harper JW, Moffat J, Rotin D, Schulman BA, Sidhu SS Mol Cell. 2016 Apr 7;62(1):121-36. doi: 10.1016/j.molcel.2016.02.005. Epub 2016, Mar 3. PMID:26949039<ref>PMID:26949039</ref>
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Description: CRYSTAL STRUCTURE OF E3 LIGASE ITCH WITH A UB VARIANT
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Sidhu, S]]
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<div class="pdbe-citations 5c7m" style="background-color:#fffaf0;"></div>
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[[Category: Dong, A]]
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[[Category: Zhang, W]]
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==See Also==
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[[Category: Wernimont, A]]
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*[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]]
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[[Category: Walker, J.R]]
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== References ==
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[[Category: Bountra, C]]
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<references/>
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[[Category: Arrowsmith, C.H]]
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__TOC__
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[[Category: Hu, J]]
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</StructureSection>
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[[Category: Tong, Y]]
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[[Category: Homo sapiens]]
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[[Category: Edwards, A.M]]
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[[Category: Large Structures]]
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[[Category: Structural Genomics Consortium (Sgc)]]
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[[Category: Arrowsmith CH]]
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[[Category: Bountra C]]
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[[Category: Dong A]]
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[[Category: Edwards AM]]
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[[Category: Hu J]]
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[[Category: Sidhu S]]
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[[Category: Tong Y]]
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[[Category: Walker JR]]
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[[Category: Wernimont A]]
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[[Category: Zhang W]]

Current revision

CRYSTAL STRUCTURE OF E3 LIGASE ITCH WITH A UB VARIANT

PDB ID 5c7m

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