6yxi
From Proteopedia
(Difference between revisions)
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<StructureSection load='6yxi' size='340' side='right'caption='[[6yxi]], [[Resolution|resolution]] 1.34Å' scene=''> | <StructureSection load='6yxi' size='340' side='right'caption='[[6yxi]], [[Resolution|resolution]] 1.34Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'> | + | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YXI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YXI 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]] 1.34Å</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]] 1.34Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PZ8:1-(3-chlorophenyl)-2,5-dimethyl-pyrrole-3-carboxylic+acid'>PZ8</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PZ8:1-(3-chlorophenyl)-2,5-dimethyl-pyrrole-3-carboxylic+acid'>PZ8</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=6yxi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yxi OCA], [https://pdbe.org/6yxi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yxi RCSB], [https://www.ebi.ac.uk/pdbsum/6yxi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yxi ProSAT]</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=6yxi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yxi OCA], [https://pdbe.org/6yxi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yxi RCSB], [https://www.ebi.ac.uk/pdbsum/6yxi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yxi ProSAT]</span></td></tr> | ||
</table> | </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 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 6yxi" style="background-color:#fffaf0;"></div> | ||
==See Also== | ==See Also== | ||
*[[Carboxylesterase 3D structures|Carboxylesterase 3D structures]] | *[[Carboxylesterase 3D structures|Carboxylesterase 3D structures]] | ||
| - | == References == | ||
| - | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| - | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Hillier J]] | [[Category: Hillier J]] | ||
Current revision
Structure of Notum in complex with a 1-(3-Chlorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid inhibitor
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Categories: Large Structures | Hillier J | Jones EY | Ruza RR | Vecchia L | Zhao Y
