4zg9

Structural basis for inhibition of human autotaxin by four novel compounds

spinqualitylabelsall models 4zg9, resolution 2.95Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4zg9 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 2.95Å Ligands: 4O2, BMA, CA, EDO, NA, NAG, ZN 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. 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 Here we present the crystal structures of human ATX in complex with four previously unpublished, structurally distinct ATX inhibitors.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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Ectonucleotide pyrophosphatase/phosphodiesterase 3D structures

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