4zg7

Structural basis for inhibition of human autotaxin by four novel compoundsStructural basis for inhibition of human autotaxin by four novel compounds

Structural highlights

4zg7 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.75Å
Ligands:	, , , , , , ,
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 Here we present the crystal structures of human ATX in complex with four previously unpublished, structurally distinct ATX inhibitors.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

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OCA

[1] 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

[2] 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

[3] 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

[4] 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

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