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5lia

From Proteopedia

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Crystal structure of murine autotaxin in complex with a small molecule inhibitor

Structural highlights

5lia is a 1 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.92Å
Ligands:	, , , , , , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ENPP2_MOUSE Note=May contribute to obesity.

Function

ENPP2_MOUSE 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 PubMed

The autotoxin-lysophosphatidic acid (ATX-LPA) axis has been implicated in several disease conditions including inflammation, fibrosis and cancer. This makes ATX an attractive drug target and its inhibition may lead to useful therapeutic agents. Through a high throughput screen (HTS) we identified a series of small molecule inhibitors of ATX which have subsequently been optimized for potency, selectivity and developability properties. This has delivered drug-like compounds such as 9v (CRT0273750) which modulate LPA levels in plasma and are suitable for in vivo studies. X-ray crystallography has revealed that these compounds have an unexpected binding mode in that they do not interact with the active site zinc ions but instead occupy the hydrophobic LPC pocket extending from the active of ATX together with the occupying the LPA 'exit' channel.

Discovery of potent inhibitors of the lysophospholipase autotaxin.,Shah P, Cheasty A, Foxton C, Raynham T, Farooq M, Gutierrez IF, Lejeune A, Pritchard M, Turnbull A, Pang L, Owen P, Boyd S, Stowell A, Jordan A, Hamilton NM, Hitchin JR, Stockley M, MacDonald E, Quesada MJ, Trivier E, Skeete J, Ovaa H, Moolenaar WH, Ryder H Bioorg Med Chem Lett. 2016 Oct 14. pii: S0960-894X(16)31064-2. doi:, 10.1016/j.bmcl.2016.10.036. PMID:27780639^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Boucher J, Quilliot D, Praderes JP, Simon MF, Gres S, Guigne C, Prevot D, Ferry G, Boutin JA, Carpene C, Valet P, Saulnier-Blache JS. Potential involvement of adipocyte insulin resistance in obesity-associated up-regulation of adipocyte lysophospholipase D/autotaxin expression. Diabetologia. 2005 Mar;48(3):569-77. Epub 2005 Feb 8. PMID:15700135 doi:10.1007/s00125-004-1660-8
↑ Pradere JP, Tarnus E, Gres S, Valet P, Saulnier-Blache JS. Secretion and lysophospholipase D activity of autotaxin by adipocytes are controlled by N-glycosylation and signal peptidase. Biochim Biophys Acta. 2007 Jan;1771(1):93-102. Epub 2006 Dec 6. PMID:17208043 doi:10.1016/j.bbalip.2006.11.010
↑ Nishimasu H, Okudaira S, Hama K, Mihara E, Dohmae N, Inoue A, Ishitani R, Takagi J, Aoki J, Nureki O. Crystal structure of autotaxin and insight into GPCR activation by lipid mediators. Nat Struct Mol Biol. 2011 Feb;18(2):205-12. doi: 10.1038/nsmb.1998. Epub 2011 Jan, 16. PMID:21240269 doi:10.1038/nsmb.1998
↑ Shah P, Cheasty A, Foxton C, Raynham T, Farooq M, Gutierrez IF, Lejeune A, Pritchard M, Turnbull A, Pang L, Owen P, Boyd S, Stowell A, Jordan A, Hamilton NM, Hitchin JR, Stockley M, MacDonald E, Quesada MJ, Trivier E, Skeete J, Ovaa H, Moolenaar WH, Ryder H. Discovery of potent inhibitors of the lysophospholipase autotaxin. Bioorg Med Chem Lett. 2016 Oct 14. pii: S0960-894X(16)31064-2. doi:, 10.1016/j.bmcl.2016.10.036. PMID:27780639 doi:http://dx.doi.org/10.1016/j.bmcl.2016.10.036

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5lia"

@@ Line 1: / Line 1: @@
 ==Crystal structure of murine autotaxin in complex with a small molecule inhibitor==
-<StructureSection load='5lia' size='340' side='right' caption='[[5lia]], [[Resolution|resolution]] 1.92&Aring;' scene=''>
+<StructureSection load='5lia' size='340' side='right'caption='[[5lia]], [[Resolution|resolution]] 1.92&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5lia]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LIA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LIA FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5lia]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LIA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5LIA FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6XN:~{N}-[(1~{S})-1-(4-CHLOROPHENYL)ETHYL]-3-[3-[[4-(TRIFLUOROMETHYLOXY)PHENYL]METHYL]IMIDAZO[4,5-B]PYRIDIN-2-YL]PROPANAMIDE'>6XN</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</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=SO4:SULFATE+ION'>SO4</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]] 1.92&#8491;</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6XN:~{N}-[(1~{S})-1-(4-CHLOROPHENYL)ETHYL]-3-[3-[[4-(TRIFLUOROMETHYLOXY)PHENYL]METHYL]IMIDAZO[4,5-B]PYRIDIN-2-YL]PROPANAMIDE'>6XN</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</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=SO4:SULFATE+ION'>SO4</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5lia FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lia OCA], [http://pdbe.org/5lia PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5lia RCSB], [http://www.ebi.ac.uk/pdbsum/5lia PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5lia 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=5lia FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lia OCA], [https://pdbe.org/5lia PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5lia RCSB], [https://www.ebi.ac.uk/pdbsum/5lia PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5lia ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/ENPP2_MOUSE ENPP2_MOUSE]] Note=May contribute to obesity.
+[https://www.uniprot.org/uniprot/ENPP2_MOUSE ENPP2_MOUSE] Note=May contribute to obesity.
 == Function ==
-[[http://www.uniprot.org/uniprot/ENPP2_MOUSE ENPP2_MOUSE]] 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.<ref>PMID:15700135</ref> <ref>PMID:17208043</ref> <ref>PMID:21240269</ref>
+[https://www.uniprot.org/uniprot/ENPP2_MOUSE ENPP2_MOUSE] 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.<ref>PMID:15700135</ref> <ref>PMID:17208043</ref> <ref>PMID:21240269</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 21: / Line 21: @@
 </div>
 <div class="pdbe-citations 5lia" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Ectonucleotide pyrophosphatase/phosphodiesterase 3D structures|Ectonucleotide pyrophosphatase/phosphodiesterase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Alkylglycerophosphoethanolamine phosphodiesterase]]
+[[Category: Large Structures]]
-[[Category: Cheasty, A]]
+[[Category: Mus musculus]]
-[[Category: Owen, P]]
+[[Category: Cheasty A]]
-[[Category: Pang, L]]
+[[Category: Owen P]]
-[[Category: Raynham, T]]
+[[Category: Pang L]]
-[[Category: Shah, P]]
+[[Category: Raynham T]]
-[[Category: Turnbull, A P]]
+[[Category: Shah P]]
-[[Category: Autotaxin]]
+[[Category: Turnbull AP]]
-[[Category: Enpp2]]
-[[Category: Hydrolase]]
-[[Category: Lysophospholipase d]]

5lia

From Proteopedia

Current revision

Crystal structure of murine autotaxin in complex with a small molecule inhibitor

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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