8c3p

Crystal structure of autotaxin gamma in complex with LPA 18:1Crystal structure of autotaxin gamma in complex with LPA 18:1

Structural highlights

8c3p is a 2 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 2.38Å
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 an enzyme primarily known for the production of lysophosphatidic acid. Being involved in the development of major human diseases, such as cancer and neurodegenerative diseases, the enzyme has been featured in multiple studies as a pharmacological target. We previously found that the cannabinoid tetrahydrocannabinol (THC) could bind and act as an excellent inhibitor of ATX. This study aims to use the cannabinoid scaffold as a starting point to find cannabinoid-unrelated ATX inhibitors, following a funnel down approach in which large chemical libraries sharing chemical similarities with THC were screened to identify lead scaffold types for optimization. This approach allowed us to identify compounds bearing chromone and indole scaffolds as promising ATX inhibitors. Further optimization led to MEY-003, which is characterized by the direct linkage of an N-pentyl indole to the 5,7-dihydroxychromone moiety. This molecule has potent inhibitory activity towards ATX-beta and ATX-É£ as evidenced by enzymatic studies and its mode of action was rationalized by structural biology studies using macromolecular X-ray crystallography.

Discovery of potent chromone-based autotaxin inhibitors inspired by cannabinoids.,Eymery MC, Nguyen KA, Basu S, Hausmann J, Tran-Nguyen VK, Seidel HP, Gutierrez L, Boumendjel A, McCarthy AA Eur J Med Chem. 2024 Jan 5;263:115944. doi: 10.1016/j.ejmech.2023.115944. Epub , 2023 Nov 10. PMID:37976710^[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
↑ Eymery MC, Nguyen KA, Basu S, Hausmann J, Tran-Nguyen VK, Seidel HP, Gutierrez L, Boumendjel A, McCarthy AA. Discovery of potent chromone-based autotaxin inhibitors inspired by cannabinoids. Eur J Med Chem. 2024 Jan 5;263:115944. PMID:37976710 doi:10.1016/j.ejmech.2023.115944

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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] Eymery MC, Nguyen KA, Basu S, Hausmann J, Tran-Nguyen VK, Seidel HP, Gutierrez L, Boumendjel A, McCarthy AA. Discovery of potent chromone-based autotaxin inhibitors inspired by cannabinoids. Eur J Med Chem. 2024 Jan 5;263:115944. PMID:37976710 doi:10.1016/j.ejmech.2023.115944

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