4zg9

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Revision as of 14:34, 16 November 2017

Structural basis for inhibition of human autotaxin by four novel compounds

Structural highlights

4zg9 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , , , ,
Related:	4zg6, 4zg7, 4zga
Gene:	ENPP2, ATX, PDNP2 (HUMAN)
Activity:	Alkylglycerophosphoethanolamine phosphodiesterase, with EC number 3.1.4.39
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 PubMed

Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA). LPA is a bioactive phospholipid that regulates diverse biological processes including cell proliferation, migration, and survival/apoptosis through the activation of a family of G protein-coupled receptors. The ATX-LPA pathway has been implicated in many pathologic conditions including cancer, fibrosis, inflammation, cholestatic pruritus and pain. Therefore, ATX inhibitors represent an attractive strategy for the development of therapeutics to treat a variety of diseases. Mouse and rat ATX have been crystallized previously with LPA or small molecule inhibitors bound. Here we present the crystal structures of human ATX in complex with four previously unpublished, structurally distinct ATX inhibitors. We demonstrate that the mechanism of inhibition of each compound reflects its unique interactions with human ATX. Our studies may provide a basis for the rational design of novel ATX inhibitors.

Structural Basis for Inhibition of Human Autotaxin by Four Potent Compounds with Distinct Modes of Binding.,Stein AJ, Bain G, Prodanovich P, Santini AM, Darlington J, Stelzer NM, Sidhu RS, Schaub J, Goulet L, Lonergan D, Calderon I, Evans JF, Hutchinson JH Mol Pharmacol. 2015 Sep 14. pii: mol.115.100404. PMID:26371182^[4]

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

References

↑ Nam SW, Clair T, Kim YS, McMarlin A, Schiffmann E, Liotta LA, Stracke ML. Autotaxin (NPP-2), a metastasis-enhancing motogen, is an angiogenic factor. Cancer Res. 2001 Sep 15;61(18):6938-44. PMID:11559573
↑ Stracke ML, Krutzsch HC, Unsworth EJ, Arestad A, Cioce V, Schiffmann E, Liotta LA. Identification, purification, and partial sequence analysis of autotaxin, a novel motility-stimulating protein. J Biol Chem. 1992 Feb 5;267(4):2524-9. PMID:1733949
↑ Hausmann J, Kamtekar S, Christodoulou E, Day JE, Wu T, Fulkerson Z, Albers HM, van Meeteren LA, Houben AJ, van Zeijl L, Jansen S, Andries M, Hall T, Pegg LE, Benson TE, Kasiem M, Harlos K, Kooi CW, Smyth SS, Ovaa H, Bollen M, Morris AJ, Moolenaar WH, Perrakis A. Structural basis of substrate discrimination and integrin binding by autotaxin. Nat Struct Mol Biol. 2011 Feb;18(2):198-204. Epub 2011 Jan 16. PMID:21240271 doi:10.1038/nsmb.1980
↑ Stein AJ, Bain G, Prodanovich P, Santini AM, Darlington J, Stelzer NM, Sidhu RS, Schaub J, Goulet L, Lonergan D, Calderon I, Evans JF, Hutchinson JH. Structural Basis for Inhibition of Human Autotaxin by Four Potent Compounds with Distinct Modes of Binding. Mol Pharmacol. 2015 Sep 14. pii: mol.115.100404. PMID:26371182 doi:http://dx.doi.org/10.1124/mol.115.100404

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4zg9"

@@ Line 1: / Line 1: @@
 ==Structural basis for inhibition of human autotaxin by four novel compounds==
 <StructureSection load='4zg9' size='340' side='right' caption='[[4zg9]], [[Resolution|resolution]] 2.95&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4zg9]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZG9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZG9 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4zg9]] is a 2 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=4ZG9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZG9 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4O2:3-[(11AS)-6-(4-FLUOROBENZYL)-1,3-DIOXO-5,6,11,11A-TETRAHYDRO-1H-IMIDAZO[1,5 1,6]PYRIDO[3,4-B]INDOL-2(3H)-YL]PROPANOIC+ACID'>4O2</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=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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">[[4zg6|4zg6]], [[4zg7|4zg7]], [[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='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=4zg9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zg9 OCA], [http://pdbe.org/4zg9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zg9 RCSB], [http://www.ebi.ac.uk/pdbsum/4zg9 PDBsum]</span></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=4zg9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zg9 OCA], [http://pdbe.org/4zg9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zg9 RCSB], [http://www.ebi.ac.uk/pdbsum/4zg9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zg9 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 24: / Line 26: @@
 </StructureSection>
 [[Category: Alkylglycerophosphoethanolamine phosphodiesterase]]
+[[Category: Human]]
 [[Category: Bain, G]]
 [[Category: Evans, J F]]

4zg9

From Proteopedia

Revision as of 14:34, 16 November 2017

Structural basis for inhibition of human autotaxin by four novel compounds

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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