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| | ==NEDD4 HECT with covalently bound indole-based inhibitor== | | ==NEDD4 HECT with covalently bound indole-based inhibitor== |
| - | <StructureSection load='5c91' size='340' side='right' caption='[[5c91]], [[Resolution|resolution]] 2.44Å' scene=''> | + | <StructureSection load='5c91' size='340' side='right'caption='[[5c91]], [[Resolution|resolution]] 2.44Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5c91]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5C91 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5C91 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5c91]] is a 1 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=5C91 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5C91 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4YU:METHYL+(2E)-4-{[(5-METHOXY-1,2-DIMETHYL-1H-INDOL-3-YL)CARBONYL]AMINO}BUT-2-ENOATE'>4YU</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.44Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2xbf|2xbf]], [[2xbb|2xbb]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4YU:METHYL+(2E)-4-{[(5-METHOXY-1,2-DIMETHYL-1H-INDOL-3-YL)CARBONYL]AMINO}BUT-2-ENOATE'>4YU</scene></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=5c91 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5c91 OCA], [http://pdbe.org/5c91 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5c91 RCSB], [http://www.ebi.ac.uk/pdbsum/5c91 PDBsum]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5c91 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5c91 OCA], [https://pdbe.org/5c91 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5c91 RCSB], [https://www.ebi.ac.uk/pdbsum/5c91 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5c91 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/NEDD4_HUMAN NEDD4_HUMAN]] 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. Involved in the pathway leading to the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase activity. Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes. Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes. According to PubMed:18562292 the direct link between NEDD4 and PTEN regulation through polyubiquitination described in PubMed:17218260 is questionable. Involved in ubiquitination of ERBB4 intracellular domain E4ICD. Involved in the budding of many viruses. Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development. Ubiquitinates TNK2 and regulates EGF-induced degradation of EGFR and TNF2.<ref>PMID:17218260</ref> <ref>PMID:18562292</ref> <ref>PMID:20086093</ref> <ref>PMID:21765395</ref> <ref>PMID:21399620</ref> | + | [https://www.uniprot.org/uniprot/NEDD4_HUMAN NEDD4_HUMAN] 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. Involved in the pathway leading to the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase activity. Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes. Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes. According to PubMed:18562292 the direct link between NEDD4 and PTEN regulation through polyubiquitination described in PubMed:17218260 is questionable. Involved in ubiquitination of ERBB4 intracellular domain E4ICD. Involved in the budding of many viruses. Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development. Ubiquitinates TNK2 and regulates EGF-induced degradation of EGFR and TNF2.<ref>PMID:17218260</ref> <ref>PMID:18562292</ref> <ref>PMID:20086093</ref> <ref>PMID:21765395</ref> <ref>PMID:21399620</ref> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | E3 ligases are genetically implicated in many human diseases, yet E3 enzyme mechanisms are not fully understood, and there is a strong need for pharmacological probes of E3s. We report the discovery that the HECT E3 Nedd4-1 is a processive enzyme and that disruption of its processivity by biochemical mutations or small molecules switches Nedd4-1 from a processive to a distributive mechanism of polyubiquitin chain synthesis. Furthermore, we discovered and structurally characterized the first covalent inhibitor of Nedd4-1, which switches Nedd4-1 from a processive to a distributive mechanism. To visualize the binding mode of the Nedd4-1 inhibitor, we used X-ray crystallography and solved the first structure of a Nedd4-1 family ligase bound to an inhibitor. Importantly, our study shows that processive Nedd4-1, but not the distributive Nedd4-1:inhibitor complex, is able to synthesize polyubiquitin chains on the substrate in the presence of the deubiquitinating enzyme USP8. Therefore, inhibition of E3 ligase processivity is a viable strategy to design E3 inhibitors. Our study provides fundamental insights into the HECT E3 mechanism and uncovers a novel class of HECT E3 inhibitors. |
| | + | |
| | + | A Small Molecule That Switches a Ubiquitin Ligase From a Processive to a Distributive Enzymatic Mechanism.,Kathman SG, Span I, Smith AT, Xu Z, Zhan J, Rosenzweig AC, Statsyuk AV J Am Chem Soc. 2015 Oct 7;137(39):12442-5. doi: 10.1021/jacs.5b06839. Epub 2015, Sep 22. PMID:26371805<ref>PMID:26371805</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 5c91" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Kathman, S]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Rosenzweig, A C]] | + | [[Category: Large Structures]] |
| - | [[Category: Smith, A T]] | + | [[Category: Kathman S]] |
| - | [[Category: Span, I]] | + | [[Category: Rosenzweig AC]] |
| - | [[Category: Statsyuk, A V]] | + | [[Category: Smith AT]] |
| - | [[Category: Hect]] | + | [[Category: Span I]] |
| - | [[Category: Inhibitor]] | + | [[Category: Statsyuk AV]] |
| - | [[Category: Ligase]]
| + | |
| - | [[Category: Ligase-ligase inhibitor complex]]
| + | |
| - | [[Category: Nedd4]]
| + | |
| Structural highlights
Function
NEDD4_HUMAN 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. Involved in the pathway leading to the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase activity. Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes. Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes. According to PubMed:18562292 the direct link between NEDD4 and PTEN regulation through polyubiquitination described in PubMed:17218260 is questionable. Involved in ubiquitination of ERBB4 intracellular domain E4ICD. Involved in the budding of many viruses. Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development. Ubiquitinates TNK2 and regulates EGF-induced degradation of EGFR and TNF2.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
E3 ligases are genetically implicated in many human diseases, yet E3 enzyme mechanisms are not fully understood, and there is a strong need for pharmacological probes of E3s. We report the discovery that the HECT E3 Nedd4-1 is a processive enzyme and that disruption of its processivity by biochemical mutations or small molecules switches Nedd4-1 from a processive to a distributive mechanism of polyubiquitin chain synthesis. Furthermore, we discovered and structurally characterized the first covalent inhibitor of Nedd4-1, which switches Nedd4-1 from a processive to a distributive mechanism. To visualize the binding mode of the Nedd4-1 inhibitor, we used X-ray crystallography and solved the first structure of a Nedd4-1 family ligase bound to an inhibitor. Importantly, our study shows that processive Nedd4-1, but not the distributive Nedd4-1:inhibitor complex, is able to synthesize polyubiquitin chains on the substrate in the presence of the deubiquitinating enzyme USP8. Therefore, inhibition of E3 ligase processivity is a viable strategy to design E3 inhibitors. Our study provides fundamental insights into the HECT E3 mechanism and uncovers a novel class of HECT E3 inhibitors.
A Small Molecule That Switches a Ubiquitin Ligase From a Processive to a Distributive Enzymatic Mechanism.,Kathman SG, Span I, Smith AT, Xu Z, Zhan J, Rosenzweig AC, Statsyuk AV J Am Chem Soc. 2015 Oct 7;137(39):12442-5. doi: 10.1021/jacs.5b06839. Epub 2015, Sep 22. PMID:26371805[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Wang X, Trotman LC, Koppie T, Alimonti A, Chen Z, Gao Z, Wang J, Erdjument-Bromage H, Tempst P, Cordon-Cardo C, Pandolfi PP, Jiang X. NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell. 2007 Jan 12;128(1):129-39. PMID:17218260 doi:10.1016/j.cell.2006.11.039
- ↑ Fouladkou F, Landry T, Kawabe H, Neeb A, Lu C, Brose N, Stambolic V, Rotin D. The ubiquitin ligase Nedd4-1 is dispensable for the regulation of PTEN stability and localization. Proc Natl Acad Sci U S A. 2008 Jun 24;105(25):8585-90. doi:, 10.1073/pnas.0803233105. Epub 2008 Jun 18. PMID:18562292 doi:10.1073/pnas.0803233105
- ↑ Lin Q, Wang J, Childress C, Sudol M, Carey DJ, Yang W. HECT E3 ubiquitin ligase Nedd4-1 ubiquitinates ACK and regulates epidermal growth factor (EGF)-induced degradation of EGF receptor and ACK. Mol Cell Biol. 2010 Mar;30(6):1541-54. doi: 10.1128/MCB.00013-10. Epub 2010 Jan, 19. PMID:20086093 doi:10.1128/MCB.00013-10
- ↑ Persaud A, Alberts P, Hayes M, Guettler S, Clarke I, Sicheri F, Dirks P, Ciruna B, Rotin D. Nedd4-1 binds and ubiquitylates activated FGFR1 to control its endocytosis and function. EMBO J. 2011 Jul 15;30(16):3259-73. doi: 10.1038/emboj.2011.234. PMID:21765395 doi:10.1038/emboj.2011.234
- ↑ Maspero E, Mari S, Valentini E, Musacchio A, Fish A, Pasqualato S, Polo S. Structure of the HECT:ubiquitin complex and its role in ubiquitin chain elongation. EMBO Rep. 2011 Mar 11. PMID:21399620 doi:10.1038/embor.2011.21
- ↑ Kathman SG, Span I, Smith AT, Xu Z, Zhan J, Rosenzweig AC, Statsyuk AV. A Small Molecule That Switches a Ubiquitin Ligase From a Processive to a Distributive Enzymatic Mechanism. J Am Chem Soc. 2015 Oct 7;137(39):12442-5. doi: 10.1021/jacs.5b06839. Epub 2015, Sep 22. PMID:26371805 doi:http://dx.doi.org/10.1021/jacs.5b06839
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