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| ==Structure-Based Design of a Novel Class of Autotaxin Inhibitors Based on Endogenous Allosteric Modulators== | | ==Structure-Based Design of a Novel Class of Autotaxin Inhibitors Based on Endogenous Allosteric Modulators== |
| <StructureSection load='7z0n' size='340' side='right'caption='[[7z0n]], [[Resolution|resolution]] 2.40Å' scene=''> | | <StructureSection load='7z0n' size='340' side='right'caption='[[7z0n]]' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[7z0n]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7Z0N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7Z0N FirstGlance]. <br> | | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7Z0N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7Z0N FirstGlance]. <br> |
| </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=I8K:[4-[1-[(4~{R})-4-[(3~{R},5~{S},7~{S},8~{R},9~{S},10~{S},13~{R},14~{S},17~{R})-10,13-dimethyl-3,7-bis(oxidanyl)-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1~{H}-cyclopenta[a]phenanthren-17-yl]pentanoyl]piperidin-4-yl]oxyphenyl]-bis(oxidanyl)-$l^{4}-borane'>I8K</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | | </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=7z0n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7z0n OCA], [https://pdbe.org/7z0n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7z0n RCSB], [https://www.ebi.ac.uk/pdbsum/7z0n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7z0n ProSAT]</span></td></tr> |
| <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Alkylglycerophosphoethanolamine_phosphodiesterase Alkylglycerophosphoethanolamine phosphodiesterase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.39 3.1.4.39] </span></td></tr>
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| <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7z0n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7z0n OCA], [https://pdbe.org/7z0n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7z0n RCSB], [https://www.ebi.ac.uk/pdbsum/7z0n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7z0n ProSAT]</span></td></tr> | |
| </table> | | </table> |
| <div style="background-color:#fffaf0;">
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| == Publication Abstract from PubMed ==
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| Autotaxin (ATX) facilitates the hydrolysis of lysophosphatidylcholine to lysophosphatidic acid (LPA), a bioactive phospholipid, which facilitates a diverse range of cellular effects in multiple tissue types. Abnormal LPA expression can lead to the progression of diseases such as cancer and fibrosis. Previously, we identified a potent ATX steroid-derived hybrid (partially orthosteric and allosteric) inhibitor which did not form interactions with the catalytic site. Herein, we describe the design, synthesis, and biological evaluation of a focused library of novel steroid-derived analogues targeting the bimetallic catalytic site, representing an entirely unique class of ATX inhibitors of type V designation, which demonstrate significant pathway-relevant biochemical and phenotypic biological effects. The current compounds modulated LPA-mediated ATX allostery and achieved indirect blockage of LPA1 internalization, in line with the observed reduction in downstream signaling cascades and chemotaxis induction. These novel type V ATX inhibitors represent a promising tool to inactivate the ATX-LPA signaling axis.
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| Structure-Based Design of a Novel Class of Autotaxin Inhibitors Based on Endogenous Allosteric Modulators.,Clark JM, Salgado-Polo F, Macdonald SJF, Barrett TN, Perrakis A, Jamieson C J Med Chem. 2022 Apr 28;65(8):6338-6351. doi: 10.1021/acs.jmedchem.2c00368. Epub , 2022 Apr 20. PMID:35440138<ref>PMID:35440138</ref>
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| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| <div class="pdbe-citations 7z0n" style="background-color:#fffaf0;"></div>
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| == References ==
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| <references/>
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| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Alkylglycerophosphoethanolamine phosphodiesterase]]
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| [[Category: Large Structures]] | | [[Category: Large Structures]] |
| [[Category: Barrett, T N]] | | [[Category: Barrett TN]] |
| [[Category: Clark, J M]] | | [[Category: Clark JM]] |
| [[Category: Jamieson, A]] | | [[Category: Jamieson A]] |
| [[Category: Macdonald, S J.F]] | | [[Category: Macdonald SJF]] |
| [[Category: Perrakis, A]] | | [[Category: Perrakis A]] |
| [[Category: Salgado-Polo, F]] | | [[Category: Salgado-Polo F]] |
| [[Category: Autotaxin]]
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| [[Category: Cancer]]
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| [[Category: Enpp2]]
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| [[Category: Fibrosis]]
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| [[Category: Hydrolase]]
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| [[Category: Lysophosphatidic acid]]
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| [[Category: Steroid]]
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