6tr5: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
The | ==Melatonin-Notum complex== | ||
<StructureSection load='6tr5' size='340' side='right'caption='[[6tr5]], [[Resolution|resolution]] 1.51Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6tr5]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TR5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6TR5 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=ML1:N-[2-(5-METHOXY-1H-INDOL-3-YL)ETHYL]ACETAMIDE'>ML1</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NOTUM, OK/SW-CL.30 ([http://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'>[http://en.wikipedia.org/wiki/[Wnt_protein]_O-palmitoleoyl-L-serine_hydrolase [Wnt protein] O-palmitoleoyl-L-serine hydrolase], with EC number [http://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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6tr5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tr5 OCA], [http://pdbe.org/6tr5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6tr5 RCSB], [http://www.ebi.ac.uk/pdbsum/6tr5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6tr5 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://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> | ||
<div class="pdbe-citations 6tr5" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Jones, E Y]] | |||
[[Category: Zhao, Y]] | [[Category: Zhao, Y]] | ||
[[Category: | [[Category: Hydrolase]] | ||
[[Category: Wnt notum inhibitor melatonin]] | |||
Revision as of 10:39, 19 February 2020
Melatonin-Notum complexMelatonin-Notum complex
Structural highlights
Function[NOTUM_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
|
| ||||||||||||||||||||