7b2y
From Proteopedia
(Difference between revisions)
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==Notum complex with ARUK3003910== | ==Notum complex with ARUK3003910== | ||
| - | <StructureSection load='7b2y' size='340' side='right'caption='[[7b2y]]' scene=''> | + | <StructureSection load='7b2y' size='340' side='right'caption='[[7b2y]], [[Resolution|resolution]] 1.23Å' 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=7B2Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7B2Y FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7b2y]] 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=7B2Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7B2Y 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=7b2y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7b2y OCA], [https://pdbe.org/7b2y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7b2y RCSB], [https://www.ebi.ac.uk/pdbsum/7b2y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7b2y 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=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SRQ:2,2-bis(fluoranyl)ethyl+4-(2,3-dihydroindol-1-yl)-4-oxidanylidene-butanoate'>SRQ</scene></td></tr> |
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NOTUM, OK/SW-CL.30 ([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/[Wnt_protein]_O-palmitoleoyl-L-serine_hydrolase [Wnt protein] O-palmitoleoyl-L-serine hydrolase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.98 3.1.1.98] </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=7b2y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7b2y OCA], [https://pdbe.org/7b2y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7b2y RCSB], [https://www.ebi.ac.uk/pdbsum/7b2y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7b2y ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [[https://www.uniprot.org/uniprot/NOTUM_HUMAN NOTUM_HUMAN]] May deacetylate GlcNAc residues on cell surface glycans. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The carboxylesterase Notum hydrolyzes a palmitoleate moiety from Wingless/Integrated(Wnt) ligands and deactivates Wnt signaling. Notum inhibitors can restore Wnt signaling which may be of therapeutic benefit for pathologies such as osteoporosis and Alzheimer's disease. We report the identification of a novel class of covalent Notum inhibitors, 4-(indolin-1-yl)-4-oxobutanoate esters. High-resolution crystal structures of the Notum inhibitor complexes reveal a common covalent adduct formed between the nucleophile serine-232 and hydrolyzed butyric esters. The covalent interaction in solution was confirmed by mass spectrometry analysis. Inhibitory potencies vary depending on the warheads used. Mechanistically, the resulting acyl-enzyme intermediate carbonyl atom is positioned at an unfavorable angle for the approach of the active site water, which, combined with strong hydrophobic interactions with the enzyme pocket residues, hinders the intermediate from being further processed and results in covalent inhibition. These insights into Notum catalytic inhibition may guide development of more potent Notum inhibitors. | ||
| + | |||
| + | Structural Insights into Notum Covalent Inhibition.,Zhao Y, Svensson F, Steadman D, Frew S, Monaghan A, Bictash M, Moreira T, Chalk R, Lu W, Fish PV, Jones EY J Med Chem. 2021 Jul 22. doi: 10.1021/acs.jmedchem.1c00701. PMID:34292747<ref>PMID:34292747</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7b2y" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Jone | + | [[Category: Jone, E Y]] |
| - | [[Category: Zhao Y]] | + | [[Category: Zhao, Y]] |
| + | [[Category: Hydrolase]] | ||
| + | [[Category: Notum inhibitor]] | ||
Revision as of 06:29, 25 August 2021
Notum complex with ARUK3003910
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