7z0n | pdb_00007z0n

Structure-Based Design of a Novel Class of Autotaxin Inhibitors Based on Endogenous Allosteric Modulators

spinqualitylabelsall models 7z0n, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 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: BMA, CA, GOL, I8K, IOD, MAN, NA, NAG, SCN, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Autotaxin (ATX) facilitates the hydrolysis of lysophosphatidylcholine to lysophosphatidic acid (LPA), a bioactive phospholipid, which facilitates a diverse range of cellular effects in multiple tissue types. Abnormal LPA expression can lead to the progression of diseases such as cancer and fibrosis. Previously, we identified a potent ATX steroid-derived hybrid (partially orthosteric and allosteric) inhibitor which did not form interactions with the catalytic site. Herein, we describe the design, synthesis, and biological evaluation of a focused library of novel steroid-derived analogues targeting the bimetallic catalytic site, representing an entirely unique class of ATX inhibitors of type V designation, which demonstrate significant pathway-relevant biochemical and phenotypic biological effects. The current compounds modulated LPA-mediated ATX allostery and achieved indirect blockage of LPA1 internalization, in line with the observed reduction in downstream signaling cascades and chemotaxis induction. These novel type V ATX inhibitors represent a promising tool to inactivate the ATX-LPA signaling axis. Structure-Based Design of a Novel Class of Autotaxin Inhibitors Based on Endogenous Allosteric Modulators.,Clark JM, Salgado-Polo F, Macdonald SJF, Barrett TN, Perrakis A, Jamieson C J Med Chem. 2022 Apr 28;65(8):6338-6351. doi: 10.1021/acs.jmedchem.2c00368. Epub , 2022 Apr 20. PMID:35440138 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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