7arg: Difference between revisions

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-'''Unreleased structure'''
-The entry 7arg is ON HOLD  until Paper Publication
+==Notum in complex with ARUK3002704==
+<StructureSection load='7arg' size='340' side='right'caption='[[7arg]], [[Resolution|resolution]] 1.24&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7ARG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ARG 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]] 1.24&#8491;</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=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=RW8:methyl+4-(2,3-dihydroindol-1-yl)-4-oxidanylidene-butanoate'>RW8</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=7arg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7arg OCA], [https://pdbe.org/7arg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7arg RCSB], [https://www.ebi.ac.uk/pdbsum/7arg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7arg ProSAT]</span></td></tr>
+</table>
+<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.
-Authors: Zhao, Y., Jones, E.Y.
+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>
-Description: Notum in complex with ARUK3002704
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Zhao, Y]]
+<div class="pdbe-citations 7arg" style="background-color:#fffaf0;"></div>
-[[Category: Jones, E.Y]]
+==See Also==
+*[[Carboxylesterase 3D structures|Carboxylesterase 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
+[[Category: Jones EY]]
+[[Category: Zhao Y]]