This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.
Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.
7ms6
From Proteopedia
(Difference between revisions)
| Line 1: | Line 1: | ||
==Structure of USP5 zinc-finger ubiquitin binding domain co-crystallized with (2-fluoro-4-((4-phenylpiperidin-1-yl)sulfonyl)benzoyl)glycine== | ==Structure of USP5 zinc-finger ubiquitin binding domain co-crystallized with (2-fluoro-4-((4-phenylpiperidin-1-yl)sulfonyl)benzoyl)glycine== | ||
| - | <StructureSection load='7ms6' size='340' side='right'caption='[[7ms6]]' scene=''> | + | <StructureSection load='7ms6' size='340' side='right'caption='[[7ms6]], [[Resolution|resolution]] 1.55Å' 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=7MS6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MS6 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7ms6]] is a 1 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=7MS6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MS6 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=7ms6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ms6 OCA], [https://pdbe.org/7ms6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ms6 RCSB], [https://www.ebi.ac.uk/pdbsum/7ms6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ms6 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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>, <scene name='pdbligand=ZPV:N-[2-fluoro-4-(4-phenylpiperidine-1-sulfonyl)benzoyl]glycine'>ZPV</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=7ms6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ms6 OCA], [https://pdbe.org/7ms6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ms6 RCSB], [https://www.ebi.ac.uk/pdbsum/7ms6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ms6 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 7ms6" 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 (2-fluoro-4-((4-phenylpiperidin-1-yl)sulfonyl)benzoyl)glycine
| |||||||||||
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
