| Structural highlights
6leh 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 2Å |
| 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
Autotaxin (ATX, also known as ENPP2) is a predominant lysophosphatidic acid (LPA)-producing enzyme in the body, and LPA regulates various physiological functions, such as angiogenesis and wound healing, as well as pathological functions, including proliferation, metastasis, and fibrosis, via specific LPA receptors. Therefore, the ATX-LPA axis is a promising therapeutic target for dozens of diseases, including cancers, pulmonary and liver fibroses, and neuropathic pain. Previous structural studies revealed that the catalytic domain of ATX has a hydrophobic pocket and a hydrophobic channel; these serve to recognize the substrate, lysophosphatidylcholine (LPC), and deliver generated LPA to LPA receptors on the plasma membrane. Most reported ATX inhibitors bind to either the hydrophobic pocket or the hydrophobic channel. Herein, we present a unique ATX inhibitor that binds mainly to the hydrophobic pocket and also partly to the hydrophobic channel, inhibiting ATX activity with high potency and selectivity in vitro and in vivo. Notably, our inhibitor can rescue the cardia bifida (two hearts) phenotype in ATX-overexpressing zebrafish embryos.
Identification of Potent In Vivo Autotaxin Inhibitors that Bind to Both Hydrophobic Pockets and Channels in the Catalytic Domain.,Kawaguchi M, Okabe T, Okudaira S, Hama K, Kano K, Nishimasu H, Nakagawa H, Ishitani R, Kojima H, Nureki O, Aoki J, Nagano T J Med Chem. 2020 Mar 13. doi: 10.1021/acs.jmedchem.9b01967. PMID:32134652[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Kawaguchi M, Okabe T, Okudaira S, Hama K, Kano K, Nishimasu H, Nakagawa H, Ishitani R, Kojima H, Nureki O, Aoki J, Nagano T. Identification of Potent In Vivo Autotaxin Inhibitors that Bind to Both Hydrophobic Pockets and Channels in the Catalytic Domain. J Med Chem. 2020 Mar 13. doi: 10.1021/acs.jmedchem.9b01967. PMID:32134652 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b01967
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