6tr7: Difference between revisions
New page: '''Unreleased structure''' The entry 6tr7 is ON HOLD Authors: Zhao, Y., Jones, E.Y. Description: N-[2-(5-fluoro-1H-indol-3-yl)ethyl]acetamide-Notum complex [[Category: Unreleased Struc... |
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The | ==N-[2-(5-fluoro-1H-indol-3-yl)ethyl]acetamide-Notum complex== | ||
<StructureSection load='6tr7' size='340' side='right'caption='[[6tr7]], [[Resolution|resolution]] 1.47Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6tr7]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TR7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TR7 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]] 1.47Å</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=HWH:~{N}-[2-(5-fluoranyl-1~{H}-indol-3-yl)ethyl]ethanamide'>HWH</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=6tr7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tr7 OCA], [https://pdbe.org/6tr7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tr7 RCSB], [https://www.ebi.ac.uk/pdbsum/6tr7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tr7 ProSAT]</span></td></tr> | |||
</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 hormone melatonin, secreted from the pineal gland, mediates multiple physiological effects including modulation of Wnt/beta-catenin signalling. The Wnt palmitoleate lipid modification is essential for its signalling activity, while the carboxylesterase Notum can remove the lipid from Wnt and inactivate it. Notum enzyme inhibition can therefore upregulate Wnt signalling. While searching for Notum inhibitors by crystallographic fragment screening, a hit compound N-[2-(5-fluoro-1H-indol-3-yl)ethyl]acetamide that is structurally similar to melatonin, came to our attention. We then soaked melatonin and its precursor N-acetylserotonin into Notum crystals and obtained high resolution structures (</= 1.5 A) of their complexes. In each of the structures, two compound molecules bind with Notum: one at the enzyme's catalytic pocket, overlapping the space occupied by the acyl tail of the Wnt palmitoleate lipid; and the other at the edge of the pocket opposite the substrate entrance. Although the inhibitory activity of melatonin shown by in vitro enzyme assays is low (IC50 75 microM), the structural information reported here provides a basis for the design of potent and brain accessible drugs for neurodegenerative diseases such as Alzheimer's disease, in which up-regulation of Wnt signalling may be beneficial. | |||
Structural characterisation of melatonin as an inhibitor of the Wnt deacylase Notum.,Zhao Y, Ren J, Hillier J, Jones M, Lu W, Jones EY J Pineal Res. 2019 Dec 26:e12630. doi: 10.1111/jpi.12630. PMID:31876313<ref>PMID:31876313</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6tr7" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Jones EY]] | |||
[[Category: Zhao Y]] | |||
Latest revision as of 16:07, 24 January 2024
N-[2-(5-fluoro-1H-indol-3-yl)ethyl]acetamide-Notum complexN-[2-(5-fluoro-1H-indol-3-yl)ethyl]acetamide-Notum complex
Structural highlights
FunctionNOTUM_HUMAN May deacetylate GlcNAc residues on cell surface glycans. Publication Abstract from PubMedThe hormone melatonin, secreted from the pineal gland, mediates multiple physiological effects including modulation of Wnt/beta-catenin signalling. The Wnt palmitoleate lipid modification is essential for its signalling activity, while the carboxylesterase Notum can remove the lipid from Wnt and inactivate it. Notum enzyme inhibition can therefore upregulate Wnt signalling. While searching for Notum inhibitors by crystallographic fragment screening, a hit compound N-[2-(5-fluoro-1H-indol-3-yl)ethyl]acetamide that is structurally similar to melatonin, came to our attention. We then soaked melatonin and its precursor N-acetylserotonin into Notum crystals and obtained high resolution structures (</= 1.5 A) of their complexes. In each of the structures, two compound molecules bind with Notum: one at the enzyme's catalytic pocket, overlapping the space occupied by the acyl tail of the Wnt palmitoleate lipid; and the other at the edge of the pocket opposite the substrate entrance. Although the inhibitory activity of melatonin shown by in vitro enzyme assays is low (IC50 75 microM), the structural information reported here provides a basis for the design of potent and brain accessible drugs for neurodegenerative diseases such as Alzheimer's disease, in which up-regulation of Wnt signalling may be beneficial. Structural characterisation of melatonin as an inhibitor of the Wnt deacylase Notum.,Zhao Y, Ren J, Hillier J, Jones M, Lu W, Jones EY J Pineal Res. 2019 Dec 26:e12630. doi: 10.1111/jpi.12630. PMID:31876313[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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