Download MendeleyCRYSTAL STRUCTURE OF THERMOANAEROBACTERIUM XYLOLYTICUM GH116 BETA-GLUCOSIDASE WITH A COVALENTLY BOUND CYCLOPHELLITOL AZIRIDINE
Lahav, D., Liu, B., van den Berg, R.J.B.H.N., van den Nieuwendijk, A.M.C.H., Wennekes, T., Ghisaidoobe, A.T., Breen, I., Ferraz, M.J., Kuo, C.-L., Wu, L., Geurink, P.P., Ovaa, H., van der Marel, G.A., van der Stelt, M., Boot, R.G., Davies, G.J., Aerts, J.M.F.G., Overkleeft, H.S.(2017) J Am Chem Soc 40: 14192-14197
- PubMed: 28937220
- DOI: https://doi.org/10.1021/jacs.7b07352
- Primary Citation of Related Structures:
8R06 - PubMed Abstract:
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 ¦Â-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.
Organizational Affiliation:
Structural Biology Laboratory, Department of Chemistry, The University of York , York YO10 5DD, United Kingdom.
