7ms7
From Proteopedia
(Difference between revisions)
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==Structure of USP5 zinc-finger ubiquitin binding domain co-crystallized with (5-((4-(4-chlorophenyl)piperidin-1-yl)sulfonyl)picolinoyl)glycine== | ==Structure of USP5 zinc-finger ubiquitin binding domain co-crystallized with (5-((4-(4-chlorophenyl)piperidin-1-yl)sulfonyl)picolinoyl)glycine== | ||
| - | <StructureSection load='7ms7' size='340' side='right'caption='[[7ms7]]' scene=''> | + | <StructureSection load='7ms7' size='340' side='right'caption='[[7ms7]], [[Resolution|resolution]] 1.45Å' 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=7MS7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MS7 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7ms7]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MS7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MS7 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=7ms7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ms7 OCA], [https://pdbe.org/7ms7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ms7 RCSB], [https://www.ebi.ac.uk/pdbsum/7ms7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ms7 ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>, <scene name='pdbligand=ZQ1:N-{5-[4-(4-chlorophenyl)piperidine-1-sulfonyl]pyridine-2-carbonyl}glycine'>ZQ1</scene></td></tr> |
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">USP5, ISOT ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Ubiquitinyl_hydrolase_1 Ubiquitinyl hydrolase 1], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.19.12 3.4.19.12] </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=7ms7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ms7 OCA], [https://pdbe.org/7ms7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ms7 RCSB], [https://www.ebi.ac.uk/pdbsum/7ms7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ms7 ProSAT]</span></td></tr> | ||
</table> | </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 is a deubiquitinase that has been implicated in a range of diseases, including cancer, but no USP5-targeting chemical probe has been reported to date. Here, we present the progression of a chemical series that occupies the C-terminal ubiquitin-binding site of a poorly characterized zinc-finger ubiquitin binding domain (ZnF-UBD) of USP5 and competitively inhibits the catalytic activity of the enzyme. Exploration of the structure-activity relationship, complemented with crystallographic characterization of the ZnF-UBD bound to multiple ligands, led to the identification of 64, which binds to the USP5 ZnF-UBD with a KD of 2.8 muM and is selective over nine proteins containing structurally similar ZnF-UBD domains. 64 inhibits the USP5 catalytic cleavage of a di-ubiquitin substrate in an in vitro assay. This study provides a chemical and structural framework for the discovery of a chemical probe to delineate USP5 function in cells. | ||
| + | |||
| + | Structure-Activity Relationship of USP5 Inhibitors.,Mann MK, Zepeda-Velazquez CA, Gonzalez-Alvarez H, Dong A, Kiyota T, Aman AM, Loppnau P, Li Y, Wilson B, Arrowsmith CH, Al-Awar R, Harding RJ, Schapira M J Med Chem. 2021 Oct 14. doi: 10.1021/acs.jmedchem.1c00889. PMID:34648286<ref>PMID:34648286</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7ms7" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Al-Awar R]] | + | [[Category: Ubiquitinyl hydrolase 1]] |
| - | [[Category: Alvarez | + | [[Category: Al-Awar, R]] |
| - | [[Category: Aman A]] | + | [[Category: Alvarez, H G]] |
| - | [[Category: Arrowsmith | + | [[Category: Aman, A]] |
| - | [[Category: Dong A]] | + | [[Category: Arrowsmith, C H]] |
| - | [[Category: Harding | + | [[Category: Dong, A]] |
| - | [[Category: Kiyota T]] | + | [[Category: Harding, R J]] |
| - | [[Category: Mann | + | [[Category: Kiyota, T]] |
| - | [[Category: Schapira M]] | + | [[Category: Mann, M K]] |
| - | [[Category: Zepeda-Velazquez | + | [[Category: Schapira, M]] |
| + | [[Category: Zepeda-Velazquez, C A]] | ||
| + | [[Category: Hydrolase]] | ||
| + | [[Category: Hydrolase-inhibitor complex]] | ||
| + | [[Category: Ubiquitin]] | ||
| + | [[Category: Ubiquitin specific protease]] | ||
| + | [[Category: Usp]] | ||
| + | [[Category: Usp5]] | ||
Revision as of 15:51, 27 October 2021
Structure of USP5 zinc-finger ubiquitin binding domain co-crystallized with (5-((4-(4-chlorophenyl)piperidin-1-yl)sulfonyl)picolinoyl)glycine
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Categories: Human | Large Structures | Ubiquitinyl hydrolase 1 | Al-Awar, R | Alvarez, H G | Aman, A | Arrowsmith, C H | Dong, A | Harding, R J | Kiyota, T | Mann, M K | Schapira, M | Zepeda-Velazquez, C A | Hydrolase | Hydrolase-inhibitor complex | Ubiquitin | Ubiquitin specific protease | Usp | Usp5
