8r06

CRYSTAL STRUCTURE OF THERMOANAEROBACTERIUM XYLANOLYTICUM GH116 BETA-GLUCOSIDASE WITH A COVALENTLY BOUND CYCLOPHELLITOL AZIRIDINE

spinqualitylabelsall models 8r06, resolution 1.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8r06 is a 1 chain structure with sequence from Thermoanaerobacterium xylanolyticum LX-11. This structure supersedes the now removed PDB entry 5ncx. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.7Å Ligands: CA, CL, GOL, PO8 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function F6BL85_THEXL Publication Abstract from PubMed Human nonlysosomal glucosylceramidase (GBA2) is one of several enzymes that controls levels of glycolipids and whose activity is linked to several human disease states. There is a major need to design or discover selective GBA2 inhibitors both as chemical tools and as potential therapeutic agents. Here, we describe the development of a fluorescence polarization activity-based protein profiling (FluoPol-ABPP) assay for the rapid identification, from a 350+ library of iminosugars, of GBA2 inhibitors. A focused library is generated based on leads from the FluoPol-ABPP screen and assessed on GBA2 selectivity offset against the other glucosylceramide metabolizing enzymes, glucosylceramide synthase (GCS), lysosomal glucosylceramidase (GBA), and the cytosolic retaining beta-glucosidase, GBA3. Our work, yielding potent and selective GBA2 inhibitors, also provides a roadmap for the development of high-throughput assays for identifying retaining glycosidase inhibitors by FluoPol-ABPP on cell extracts containing recombinant, overexpressed glycosidase as the easily accessible enzyme source. A Fluorescence Polarization Activity-Based Protein Profiling Assay in the Discovery of Potent, Selective Inhibitors for Human Nonlysosomal Glucosylceramidase.,Lahav D, Liu B, van den Berg RJBHN, van den Nieuwendijk AMCH, Wennekes T, Ghisaidoobe AT, Breen I, Ferraz MJ, Kuo CL, Wu L, Geurink PP, Ovaa H, van der Marel GA, van der Stelt M, Boot RG, Davies GJ, Aerts JMFG, Overkleeft HS J Am Chem Soc. 2017 Sep 29. doi: 10.1021/jacs.7b07352. PMID:28937220 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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