7xpy: Difference between revisions
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==Crystal structure of USP7 in complex with its inhibitor== | ==Crystal structure of USP7 in complex with its inhibitor== | ||
<StructureSection load='7xpy' size='340' side='right'caption='[[7xpy]]' scene=''> | <StructureSection load='7xpy' size='340' side='right'caption='[[7xpy]], [[Resolution|resolution]] 2.35Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7XPY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7XPY FirstGlance]. <br> | <table><tr><td colspan='2'>[[7xpy]] 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=7XPY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7XPY FirstGlance]. <br> | ||
</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=7xpy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7xpy OCA], [https://pdbe.org/7xpy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7xpy RCSB], [https://www.ebi.ac.uk/pdbsum/7xpy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7xpy ProSAT]</span></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]] 2.35Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EIB:[(3S,3aR,4R,6Z,9S,10E,11aR)-9-acetyloxy-6-(acetyloxymethyl)-3,10-dimethyl-2-oxidanylidene-3a,4,5,8,9,11a-hexahydro-3H-cyclodeca[b]furan-4-yl]+(E)-2-methyl-4-oxidanyl-but-2-enoate'>EIB</scene></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=7xpy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7xpy OCA], [https://pdbe.org/7xpy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7xpy RCSB], [https://www.ebi.ac.uk/pdbsum/7xpy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7xpy ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/UBP7_HUMAN UBP7_HUMAN] Hydrolase that deubiquitinates target proteins such as FOXO4, p53/TP53, MDM2, ERCC6, DNMT1, UHRF1, PTEN and DAXX. Together with DAXX, prevents MDM2 self-ubiquitination and enhances the E3 ligase activity of MDM2 towards p53/TP53, thereby promoting p53/TP53 ubiquitination and proteasomal degradation. Deubiquitinates p53/TP53 and MDM2 and strongly stabilizes p53/TP53 even in the presence of excess MDM2, and also induces p53/TP53-dependent cell growth repression and apoptosis. Deubiquitination of FOXO4 in presence of hydrogen peroxide is not dependent on p53/TP53 and inhibits FOXO4-induced transcriptional activity. In association with DAXX, is involved in the deubiquitination and translocation of PTEN from the nucleus to the cytoplasm, both processes that are counteracted by PML. Involved in cell proliferation during early embryonic development. Involved in transcription-coupled nucleotide excision repair (TC-NER) in response to UV damage: recruited to DNA damage sites following interaction with KIAA1530/UVSSA and promotes deubiquitination of ERCC6, preventing UV-induced degradation of ERCC6. Contributes to the overall stabilization and trans-activation capability of the herpesvirus 1 trans-acting transcriptional protein ICP0/VMW110 during HSV-1 infection. Involved in maintenance of DNA methylation via its interaction with UHRF1 and DNMT1: acts by mediating deubiquitination of UHRF1 and DNMT1, preventing their degradation and promoting DNA methylation by DNMT1. Exhibits a preference towards 'Lys-48'-linked Ubiquitin chains.<ref>PMID:11923872</ref> <ref>PMID:14506283</ref> <ref>PMID:15053880</ref> <ref>PMID:16160161</ref> <ref>PMID:16964248</ref> <ref>PMID:18716620</ref> <ref>PMID:18590780</ref> <ref>PMID:20153724</ref> <ref>PMID:21745816</ref> <ref>PMID:22411829</ref> <ref>PMID:22689415</ref> <ref>PMID:22466611</ref> <ref>PMID:22466612</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Neuroinflammation is a fundamental contributor to progressive neuronal damage, which arouses a heightened interest in neurodegenerative disease therapy. Ubiquitin-specific protease 7 (USP7) has a crucial role in regulating protein stability in multiple biological processes; however, the potential role of USP7 in neurodegenerative progression is poorly understood. Here, we discover the natural small molecule eupalinolide B (EB), which targets USP7 to inhibit microglia activation. Cocrystal structure reveals a previously undisclosed covalent allosteric site, Cys(576), in a unique noncatalytic HUBL domain. By selectively modifying Cys(576), EB allosterically inhibits USP7 to cause a ubiquitination-dependent degradation of Keap1. Keap1 function loss further results in an Nrf2-dependent transcription activation of anti-neuroinflammation genes in microglia. In vivo, pharmacological USP7 inhibition attenuates microglia activation and resultant neuron injury, thereby notably improving behavioral deficits in dementia and Parkinson's disease mouse models. Collectively, our findings provide an attractive future direction for neurodegenerative disease therapy by inhibiting microglia-mediated neuroinflammation by targeting USP7. | |||
Neuroinflammation inhibition by small-molecule targeting USP7 noncatalytic domain for neurodegenerative disease therapy.,Zhang XW, Feng N, Liu YC, Guo Q, Wang JK, Bai YZ, Ye XM, Yang Z, Yang H, Liu Y, Yang MM, Wang YH, Shi XM, Liu D, Tu PF, Zeng KW Sci Adv. 2022 Aug 12;8(32):eabo0789. doi: 10.1126/sciadv.abo0789. Epub 2022 Aug, 10. PMID:35947662<ref>PMID:35947662</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7xpy" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Feng N]] | [[Category: Feng N]] | ||
[[Category: Zeng KW]] | [[Category: Zeng KW]] | ||