8R06

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

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8R06 の概要

• エントリーDOI: 10.2210/pdb8r06/pdb
• 分子名称: Glucosylceramidase, (1~{R},2~{S},3~{S},4~{S},5~{R},6~{R})-5-azanyl-6-(hydroxymethyl)cyclohexane-1,2,3,4-tetrol, CALCIUM ION, ... (6 entities in total)
• 機能のキーワード: glucosylceramidase, hydrolase
• 由来する生物種: Thermoanaerobacterium xylanolyticum LX-11
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 92248.10

構造登録者

Offen, W.A.,Davies, G.J.,Breen, I.Z. (登録日: 2023-10-30, 公開日: 2023-11-22, 最終更新日: 2024-11-13)

主引用文献

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.
CRYSTAL STRUCTURE OF THERMOANAEROBACTERIUM XYLOLYTICUM GH116 BETA-GLUCOSIDASE WITH A COVALENTLY BOUND CYCLOPHELLITOL AZIRIDINE
JACS, 40:14192-14197, 2017

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 β-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.

PubMed: 28937220
DOI: 10.1021/jacs.7b07352

実験手法

X-RAY DIFFRACTION (1.7 Å)