7z3l

Autotaxin in complex with hybrid compound ziritaxestat (GLPG1690)

spinqualitylabelsall models 7z3l, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7z3l is a 1 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.4Å Ligands: 7NB, BMA, CA, GOL, IOD, MAN, NA, NAG, SCN, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ENPP2_RAT Publication Abstract from PubMed Autotaxin (ATX; ENPP2) produces the lipid mediator lysophosphatidic acid (LPA) that signals through disparate EDG (LPA(1-3)) and P2Y (LPA(4-6)) G protein-coupled receptors. ATX/LPA promotes several (patho)physiological processes, including in pulmonary fibrosis, thus serving as an attractive drug target. However, it remains unclear if clinical outcome depends on how different types of ATX inhibitors modulate the ATX/LPA signaling axis. Here, we show that the ATX "tunnel" is crucial for conferring key aspects of ATX/LPA signaling and dictates cellular responses independent of ATX catalytic activity, with a preference for activation of P2Y LPA receptors. The efficacy of the ATX/LPA signaling responses are abrogated more efficiently by tunnel-binding inhibitors, such as ziritaxestat (GLPG1690), compared with inhibitors that exclusively target the active site, as shown in primary lung fibroblasts and a murine model of radiation-induced pulmonary fibrosis. Our results uncover a receptor-selective signaling mechanism for ATX, implying clinical benefit for tunnel-targeting ATX inhibitors. Autotaxin facilitates selective LPA receptor signaling.,Salgado-Polo F, Borza R, Matsoukas MT, Marsais F, Jagerschmidt C, Waeckel L, Moolenaar WH, Ford P, Heckmann B, Perrakis A Cell Chem Biol. 2023 Jan 19;30(1):69-84.e14. doi: 10.1016/j.chembiol.2022.12.006. , Epub 2023 Jan 13. PMID:36640760 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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