6dxh: Difference between revisions
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==Structure of USP5 zinc-finger ubiquitin binding domain co-crystallized with 4-(4-tert-butylphenyl)-4-oxobutanoate== | |||
<StructureSection load='6dxh' size='340' side='right'caption='[[6dxh]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6dxh]] 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=6DXH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DXH FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HH4:4-(4-tert-butylphenyl)-4-oxobutanoic+acid'>HH4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=6dxh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dxh OCA], [https://pdbe.org/6dxh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6dxh RCSB], [https://www.ebi.ac.uk/pdbsum/6dxh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6dxh ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/UBP5_HUMAN UBP5_HUMAN] Cleaves linear and branched multiubiquitin polymers with a marked preference for branched polymers. Involved in unanchored 'Lys-48'-linked polyubiquitin disassembly. Binds linear and 'Lys-63'-linked polyubiquitin with a lower affinity. Knock-down of USP5 causes the accumulation of p53/TP53 and an increase in p53/TP53 transcriptional activity because the unanchored polyubiquitin that accumulates is able to compete with ubiquitinated p53/TP53 but not with MDM2 for proteasomal recognition.<ref>PMID:19098288</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
USP5 disassembles unanchored polyubiquitin chains to recycle free monoubiquitin, and is one of the 12 ubiquitin specific proteases featuring a zinc finger ubiquitin-binding domain (ZnF-UBD). This distinct structural module has been associated with substrate positioning or allosteric modulation of catalytic activity, but its cellular function remains unclear. We screened a chemical library focused on the ZnF-UBD of USP5, crystallized hits in complex with the protein, and generated a preliminary structure-activity relationship, which enables the development of more potent and selective compounds. This work serves as a framework for the discovery of a chemical probe to delineate the function of USP5 ZnF-UBD in proteasomal degradation and other ubiquitin signaling pathways in health and disease. | |||
Discovery of Small Molecule Antagonists of the USP5 Zinc Finger Ubiquitin-Binding Domain.,Mann MK, Franzoni I, de Freitas RF, Tempel W, Houliston S, Smith L, Vedadi M, Arrowsmith CH, Harding RJ, Schapira M J Med Chem. 2019 Nov 27;62(22):10144-10155. doi: 10.1021/acs.jmedchem.9b00988., Epub 2019 Nov 12. PMID:31663737<ref>PMID:31663737</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6dxh" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: | ==See Also== | ||
[[Category: | *[[Thioesterase 3D structures|Thioesterase 3D structures]] | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Arrowsmith CH]] | |||
[[Category: Bountra C]] | |||
[[Category: Edwards AM]] | |||
[[Category: Ferreira de Freitas R]] | |||
[[Category: Franzoni I]] | |||
[[Category: Harding RJ]] | |||
[[Category: Mann MK]] | |||
[[Category: Ravichandran M]] | |||
[[Category: Schapira M]] | |||
Latest revision as of 12:51, 23 October 2024
Structure of USP5 zinc-finger ubiquitin binding domain co-crystallized with 4-(4-tert-butylphenyl)-4-oxobutanoateStructure of USP5 zinc-finger ubiquitin binding domain co-crystallized with 4-(4-tert-butylphenyl)-4-oxobutanoate
Structural highlights
FunctionUBP5_HUMAN Cleaves linear and branched multiubiquitin polymers with a marked preference for branched polymers. Involved in unanchored 'Lys-48'-linked polyubiquitin disassembly. Binds linear and 'Lys-63'-linked polyubiquitin with a lower affinity. Knock-down of USP5 causes the accumulation of p53/TP53 and an increase in p53/TP53 transcriptional activity because the unanchored polyubiquitin that accumulates is able to compete with ubiquitinated p53/TP53 but not with MDM2 for proteasomal recognition.[1] Publication Abstract from PubMedUSP5 disassembles unanchored polyubiquitin chains to recycle free monoubiquitin, and is one of the 12 ubiquitin specific proteases featuring a zinc finger ubiquitin-binding domain (ZnF-UBD). This distinct structural module has been associated with substrate positioning or allosteric modulation of catalytic activity, but its cellular function remains unclear. We screened a chemical library focused on the ZnF-UBD of USP5, crystallized hits in complex with the protein, and generated a preliminary structure-activity relationship, which enables the development of more potent and selective compounds. This work serves as a framework for the discovery of a chemical probe to delineate the function of USP5 ZnF-UBD in proteasomal degradation and other ubiquitin signaling pathways in health and disease. Discovery of Small Molecule Antagonists of the USP5 Zinc Finger Ubiquitin-Binding Domain.,Mann MK, Franzoni I, de Freitas RF, Tempel W, Houliston S, Smith L, Vedadi M, Arrowsmith CH, Harding RJ, Schapira M J Med Chem. 2019 Nov 27;62(22):10144-10155. doi: 10.1021/acs.jmedchem.9b00988., Epub 2019 Nov 12. PMID:31663737[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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