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==Structure-based evolution of a hybrid steroid series of Autotaxin inhibitors== | ==Structure-based evolution of a hybrid steroid series of Autotaxin inhibitors== | ||
<StructureSection load='5m0d' size='340' side='right' caption='[[5m0d]], [[Resolution|resolution]] 2.40Å' scene=''> | <StructureSection load='5m0d' size='340' side='right'caption='[[5m0d]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5m0d]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5M0D OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[5m0d]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5M0D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5M0D FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7C8:[3,5-bis(chloranyl)phenyl]methyl+4-[(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]pentyl]piperazine-1-carboxylate'>7C8</scene>, <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=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=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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]] 2.4Å</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7C8:[3,5-bis(chloranyl)phenyl]methyl+4-[(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]pentyl]piperazine-1-carboxylate'>7C8</scene>, <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=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=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=5m0d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5m0d OCA], [https://pdbe.org/5m0d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5m0d RCSB], [https://www.ebi.ac.uk/pdbsum/5m0d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5m0d ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/ENPP2_RAT ENPP2_RAT] | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 16: | Line 19: | ||
</div> | </div> | ||
<div class="pdbe-citations 5m0d" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5m0d" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Ectonucleotide pyrophosphatase/phosphodiesterase 3D structures|Ectonucleotide pyrophosphatase/phosphodiesterase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Rattus norvegicus]] | ||
[[Category: | [[Category: Heidebrecht T]] | ||
[[Category: | [[Category: Keune W-J]] | ||
[[Category: | [[Category: Perrakis A]] | ||
Latest revision as of 21:19, 1 November 2023
Structure-based evolution of a hybrid steroid series of Autotaxin inhibitorsStructure-based evolution of a hybrid steroid series of Autotaxin inhibitors
Structural highlights
FunctionPublication Abstract from PubMedAutotaxin produces the bioactive lipid lysophosphatidic acid (LPA) and is a drug target of considerable interest for numerous pathologies. We report the expedient, structure-guided evolution of weak physiological allosteric inhibitors (bile salts) into potent competitive Autotaxin inhibitors that do not interact with the catalytic site. Functional data confirms that our lead compound attenuates LPA mediated signaling in cells and reduces LPA synthesis in vivo, providing a promising natural product derived scaffold for drug discovery. Rational Design of Autotaxin Inhibitors by Structural Evolution of Endogenous Modulators.,Keune WJ, Potjewyd F, Heidebrecht T, Salgado-Polo F, Macdonald SJ, Chelvarajan L, Abdel Latif A, Soman S, Morris AJ, Watson AJ, Jamieson C, Perrakis A J Med Chem. 2017 Mar 9;60(5):2006-2017. doi: 10.1021/acs.jmedchem.6b01743. Epub, 2017 Feb 16. PMID:28165241[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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