7b3f: Difference between revisions
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<StructureSection load='7b3f' size='340' side='right'caption='[[7b3f]], [[Resolution|resolution]] 1.39Å' scene=''> | <StructureSection load='7b3f' size='340' side='right'caption='[[7b3f]], [[Resolution|resolution]] 1.39Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'> | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7B3F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7B3F FirstGlance]. <br> | ||
</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=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SRK:4-(2,3-dihydroindol-1-yl)-4-oxidanylidene-butanoic+acid'>SRK</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.39Å</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=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SRK:4-(2,3-dihydroindol-1-yl)-4-oxidanylidene-butanoic+acid'>SRK</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=7b3f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7b3f OCA], [https://pdbe.org/7b3f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7b3f RCSB], [https://www.ebi.ac.uk/pdbsum/7b3f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7b3f ProSAT]</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=7b3f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7b3f OCA], [https://pdbe.org/7b3f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7b3f RCSB], [https://www.ebi.ac.uk/pdbsum/7b3f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7b3f ProSAT]</span></td></tr> | ||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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</div> | </div> | ||
<div class="pdbe-citations 7b3f" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 7b3f" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Carboxylesterase 3D structures|Carboxylesterase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Jone | [[Category: Jone EY]] | ||
[[Category: Zhao | [[Category: Zhao Y]] | ||
Latest revision as of 09:05, 21 November 2024
Notum S232A in complex with ARUK3003718Notum S232A in complex with ARUK3003718
Structural highlights
Publication Abstract from PubMedThe 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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