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==STRUCTURE OF THE WNT DEACYLASE NOTUM IN COMPLEX WITH A PYRROLIDINE-3-CARBOXYLIC ACID FRAGMENT 587== | ==STRUCTURE OF THE WNT DEACYLASE NOTUM IN COMPLEX WITH A PYRROLIDINE-3-CARBOXYLIC ACID FRAGMENT 587== | ||
<StructureSection load='6yv0' size='340' side='right'caption='[[6yv0]]' scene=''> | <StructureSection load='6yv0' size='340' side='right'caption='[[6yv0]], [[Resolution|resolution]] 2.00Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<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 [http://proteopedia.org/fgij/fg.htm?mol=6YV0 FirstGlance]. <br> | <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> | ||
</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> | </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='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://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> | |||
From MEDLINE®/PubMed®, 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 | [[Category: Jones, E Y]] | ||
[[Category: Ruza | [[Category: Ruza, R R]] | ||
[[Category: Fragment screen]] | |||
[[Category: Frizzled]] | |||
[[Category: Fzd]] | |||
[[Category: Hydrolase]] | |||
[[Category: Notum]] | |||
[[Category: Wnt]] | |||
[[Category: Wnt signalling]] | |||