5kxa: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==Selective Inhibition of Autotaxin is Effective in Mouse Models of Liver Fibrosis== | ==Selective Inhibition of Autotaxin is Effective in Mouse Models of Liver Fibrosis== | ||
<StructureSection load='5kxa' size='340' side='right' caption='[[5kxa]], [[Resolution|resolution]] 2.59Å' scene=''> | <StructureSection load='5kxa' size='340' side='right'caption='[[5kxa]], [[Resolution|resolution]] 2.59Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5kxa]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KXA OCA]. For a <b>guided tour on the structure components</b> use [http:// | <table><tr><td colspan='2'>[[5kxa]] 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=5KXA OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5KXA FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6Y7:3-[6-CHLORANYL-2-CYCLOPROPYL-1-(1-ETHYLPYRAZOL-4-YL)-7-FLUORANYL-INDOL-3-YL]SULFANYL-2-FLUORANYL-BENZOIC+ACID'>6Y7</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6Y7:3-[6-CHLORANYL-2-CYCLOPROPYL-1-(1-ETHYLPYRAZOL-4-YL)-7-FLUORANYL-INDOL-3-YL]SULFANYL-2-FLUORANYL-BENZOIC+ACID'>6Y7</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4zg7|4zg7]], [[4zg6|4zg6]], [[4zg9|4zg9]], [[4zga|4zga]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4zg7|4zg7]], [[4zg6|4zg6]], [[4zg9|4zg9]], [[4zga|4zga]]</td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ENPP2, ATX, PDNP2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Alkylglycerophosphoethanolamine_phosphodiesterase Alkylglycerophosphoethanolamine phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.39 3.1.4.39] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Alkylglycerophosphoethanolamine_phosphodiesterase Alkylglycerophosphoethanolamine phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.39 3.1.4.39] </span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http:// | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5kxa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kxa OCA], [http://pdbe.org/5kxa PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5kxa RCSB], [http://www.ebi.ac.uk/pdbsum/5kxa PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5kxa ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
| Line 20: | Line 21: | ||
</div> | </div> | ||
<div class="pdbe-citations 5kxa" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5kxa" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Ectonucleotide pyrophosphatase/phosphodiesterase 3D structures|Ectonucleotide pyrophosphatase/phosphodiesterase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
| Line 25: | Line 29: | ||
</StructureSection> | </StructureSection> | ||
[[Category: Alkylglycerophosphoethanolamine phosphodiesterase]] | [[Category: Alkylglycerophosphoethanolamine phosphodiesterase]] | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Bain, G]] | [[Category: Bain, G]] | ||
[[Category: Evans, J F]] | [[Category: Evans, J F]] | ||
Revision as of 09:36, 5 August 2020
Selective Inhibition of Autotaxin is Effective in Mouse Models of Liver FibrosisSelective Inhibition of Autotaxin is Effective in Mouse Models of Liver Fibrosis
Structural highlights
Function[ENPP2_HUMAN] Hydrolyzes lysophospholipids to produce lysophosphatidic acid (LPA) in extracellular fluids. Major substrate is lysophosphatidylcholine. Also can act on sphingosylphosphphorylcholine producing sphingosine-1-phosphate, a modulator of cell motility. Can hydrolyze, in vitro, bis-pNPP, to some extent pNP-TMP, and barely ATP. Involved in several motility-related processes such as angiogenesis and neurite outgrowth. Acts as an angiogenic factor by stimulating migration of smooth muscle cells and microtubule formation. Stimulates migration of melanoma cells, probably via a pertussis toxin-sensitive G protein. May have a role in induction of parturition. Possible involvement in cell proliferation and adipose tissue development. Tumor cell motility-stimulating factor.[1] [2] [3] Publication Abstract from PubMedAutotaxin (ATX) is a secreted glycoprotein that converts lysophosphatidylcholine (LPC) to the bioactive phospholipid lysophosphatidic acid (LPA) and is the major enzyme generating circulating LPA. Inhibition of LPA signaling has profound antifibrotic effects in multiple organ systems, including lung, kidney, skin, and peritoneum. However, other LPA-generating pathways exist, and the role of ATX in localized tissue LPA production and fibrosis remains unclear and controversial. In this study, we describe the preclinical pharmacologic, pharmacokinetic, and pharmacodynamic properties of a novel small-molecule ATX inhibitor, PAT-505 [3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl) thio)-2-fluorobenzoic acid sodium salt]. PAT-505 is a potent, selective, noncompetitive inhibitor that displays significant inhibition of ATX activity in plasma and liver tissue after oral administration. When dosed therapeutically in a Stelic Mouse Animal Model of nonalcoholic steatohepatitis (NASH), PAT-505 treatment resulted in a small but significant improvement in fibrosis with only minor improvements in hepatocellular ballooning and hepatic inflammation. In a choline-deficient, high-fat diet model of NASH, therapeutic treatment with PAT-505 robustly reduced liver fibrosis with no significant effect on steatosis, hepatocellular ballooning, or inflammation. These data demonstrate that inhibiting autotaxin is antifibrotic and may represent a novel therapeutic approach for the treatment of multiple fibrotic liver diseases, including NASH. Selective Inhibition of Autotaxin Is Efficacious in Mouse Models of Liver Fibrosis.,Bain G, Shannon KE, Huang F, Darlington J, Goulet L, Prodanovich P, Ma GL, Santini AM, Stein AJ, Lonergan D, King CD, Calderon I, Lai A, Hutchinson JH, Evans JF J Pharmacol Exp Ther. 2017 Jan;360(1):1-13. Epub 2016 Oct 17. PMID:27754931[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||||||