6yv0: Difference between revisions

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<StructureSection load='6yv0' size='340' side='right'caption='[[6yv0]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
<StructureSection load='6yv0' size='340' side='right'caption='[[6yv0]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6yv0]] 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=6YV0 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6YV0 FirstGlance]. <br>
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YV0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YV0 FirstGlance]. <br>
</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=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PQT:(3~{R})-1-(2-chlorophenyl)pyrrolidine-3-carboxylic+acid'>PQT</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2&#8491;</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='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=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PQT:(3~{R})-1-(2-chlorophenyl)pyrrolidine-3-carboxylic+acid'>PQT</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=6yv0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yv0 OCA], [https://pdbe.org/6yv0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yv0 RCSB], [https://www.ebi.ac.uk/pdbsum/6yv0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yv0 ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6yv0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yv0 OCA], [http://pdbe.org/6yv0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6yv0 RCSB], [http://www.ebi.ac.uk/pdbsum/6yv0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6yv0 ProSAT]</span></td></tr>
</table>
</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 Wnt family of proteins are secreted signaling proteins that play key roles in regulating cellular functions. Recently, carboxylesterase Notum was shown to act as a negative regulator of Wnt signaling by mediating the removal of an essential palmitoleate. Here we disclose two new chemical scaffolds that inhibit Notum enzymatic activity. Our approach was to create a fragment library of 250 acids for screening against Notum in a biochemical assay followed by structure determination by X-ray crystallography. Twenty fragments were identified as hits for Notum inhibition, and 14 of these fragments were shown to bind in the palmitoleate pocket of Notum. Optimization of 1-phenylpyrrole 20, guided by structure-based drug design, identified 20z as the most potent compound from this series. Similarly, the optimization of 1-phenylpyrrolidine 8 gave acid 26. This work demonstrates that inhibition of Notum activity can be achieved by small, drug-like molecules possessing favorable in vitro ADME profiles.


Screening of a Custom-Designed Acid Fragment Library Identifies 1-Phenylpyrroles and 1-Phenylpyrrolidines as Inhibitors of Notum Carboxylesterase Activity.,Mahy W, Patel M, Steadman D, Woodward HL, Atkinson BN, Svensson F, Willis NJ, Flint A, Papatheodorou D, Zhao Y, Vecchia L, Ruza RR, Hillier J, Frew S, Monaghan A, Costa A, Bictash M, Walter MW, Jones EY, Fish PV J Med Chem. 2020 Aug 18. doi: 10.1021/acs.jmedchem.0c00660. PMID:32787107<ref>PMID:32787107</ref>
==See Also==
 
*[[Carboxylesterase 3D structures|Carboxylesterase 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6yv0" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Hillier, J]]
[[Category: Hillier J]]
[[Category: Jones, E Y]]
[[Category: Jones EY]]
[[Category: Ruza, R R]]
[[Category: Ruza RR]]
[[Category: Fragment screen]]
[[Category: Frizzled]]
[[Category: Fzd]]
[[Category: Hydrolase]]
[[Category: Notum]]
[[Category: Wnt]]
[[Category: Wnt signalling]]

Latest revision as of 13:46, 23 October 2024

STRUCTURE OF THE WNT DEACYLASE NOTUM IN COMPLEX WITH A PYRROLIDINE-3-CARBOXYLIC ACID FRAGMENT 587STRUCTURE OF THE WNT DEACYLASE NOTUM IN COMPLEX WITH A PYRROLIDINE-3-CARBOXYLIC ACID FRAGMENT 587

Structural highlights

Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2Å
Ligands:, , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

See Also

6yv0, resolution 2.00Å

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