6yv4

==STRUCTURE OF THE WNT DEACYLASE NOTUM IN COMPLEX WITH A PYRROLE-3-CARBOXYLIC ACID FRAGMENT 686==

<table><tr><td colspan='2'>[[6yv4]] 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=6YV4 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6YV4 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=PQK:1-cyclopropyl-2,5-dimethyl-pyrrole-3-carboxylic+acid'>PQK</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'>[http://proteopedia.org/fgij/fg.htm?mol=6yv4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yv4 OCA], [http://pdbe.org/6yv4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6yv4 RCSB], [http://www.ebi.ac.uk/pdbsum/6yv4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6yv4 ProSAT]</span></td></tr>

== Function ==

[[http://www.uniprot.org/uniprot/NOTUM_HUMAN NOTUM_HUMAN]] May deacetylate GlcNAc residues on cell surface glycans.

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== 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.

 

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== References ==

[[Category: Human]]

[[Category: Hillier, J]]

[[Category: Jones, E Y]]

[[Category: Ruza, R R]]

[[Category: Wnt signalling]]