6t2h: Difference between revisions
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<StructureSection load='6t2h' size='340' side='right'caption='[[6t2h]], [[Resolution|resolution]] 1.41Å' scene=''> | <StructureSection load='6t2h' size='340' side='right'caption='[[6t2h]], [[Resolution|resolution]] 1.41Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6t2h]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6T2H OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6t2h]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6T2H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6T2H 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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=M9N:2-[[(4~{S})-5-chloranyl-6-methyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-4-yl]sulfanyl]ethanoic+acid'>M9N</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.41Å</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=M9N:2-[[(4~{S})-5-chloranyl-6-methyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-4-yl]sulfanyl]ethanoic+acid'>M9N</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6t2h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6t2h OCA], [https://pdbe.org/6t2h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6t2h RCSB], [https://www.ebi.ac.uk/pdbsum/6t2h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6t2h ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/NOTUM_HUMAN NOTUM_HUMAN] May deacetylate GlcNAc residues on cell surface glycans. | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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</div> | </div> | ||
<div class="pdbe-citations 6t2h" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 6t2h" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Carboxylesterase 3D structures|Carboxylesterase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Jones | [[Category: Jones EY]] | ||
[[Category: Zhao | [[Category: Zhao Y]] | ||
Latest revision as of 15:53, 24 January 2024
Furano[2,3-d]prymidine amides as Notum inhibitorsFurano[2,3-d]prymidine amides as Notum inhibitors
Structural highlights
FunctionNOTUM_HUMAN May deacetylate GlcNAc residues on cell surface glycans. Publication Abstract from PubMedThe carboxylesterase Notum is a key negative regulator of the Wnt signaling pathway by mediating the depalmitoleoylation of Wnt proteins. Our objective was to discover potent small molecule inhibitors of Notum suitable for exploring the regulation of Wnt signaling in the central nervous system. Scaffold-hopping from thienopyrimidine acids 1 and 2, supported by X-ray structure determination, identified 3-methylimidazolin-4-one amides 20-24 as potent inhibitors of Notum with activity across three orthogonal assay formats (biochemical, extra-cellular, occupancy). A preferred example 24 demonstrated good stability in mouse microsomes and plasma, and cell permeability in the MDCK-MDR1 assay albeit with modest P-gp mediated efflux. Pharmacokinetic studies with 24 were performed in vivo in mouse with single oral administration of 24 showing good plasma exposure and reasonable CNS penetration. We propose that 24 is a new chemical tool suitable for cellular studies to explore the fundamental biology of Notum. Scaffold-hopping identifies furano[2,3-d]pyrimidine amides as potent Notum inhibitors.,Atkinson BN, Steadman D, Mahy W, Zhao Y, Sipthorp J, Bayle ED, Svensson F, Papageorgiou G, Jeganathan F, Frew S, Monaghan A, Bictash M, Jones EY, Fish PV Bioorg Med Chem Lett. 2019 Oct 28:126751. doi: 10.1016/j.bmcl.2019.126751. PMID:31862412[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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