6YTR

Structure of recombinant human beta-glucocerebrosidase in complex with cyclophellitol aziridine inhibitor

これはPDB形式変換不可エントリーです。

6YTR の概要

• エントリーDOI: 10.2210/pdb6ytr/pdb
• 関連するPDBエントリー: 6YTP 6YUT 6YV3 6Z39
• 分子名称: Lysosomal acid glucosylceramidase, alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• 機能のキーワード: beta-glucocerebrosidase, lysosomal glycoside hydrolase, gh30, hydrolase, cyclophellitol aziridine, inhibitor, complex
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 117012.96

構造登録者

Rowland, R.J.,Davies, G.J. (登録日: 2020-04-24, 公開日: 2021-05-12, 最終更新日: 2024-10-16)

主引用文献

Rowland, R.J.,Chen, Y.,Breen, I.,Wu, L.,Offen, W.A.,Beenakker, T.J.,Su, Q.,van den Nieuwendijk, A.M.C.H.,Aerts, J.M.F.G.,Artola, M.,Overkleeft, H.S.,Davies, G.J.
Design, Synthesis and Structural Analysis of Glucocerebrosidase Imaging Agents.
Chemistry, 27:16377-16388, 2021

PubMed Abstract: Gaucher disease (GD) is a lysosomal storage disorder caused by inherited deficiencies in β-glucocerebrosidase (GBA). Current treatments require rapid disease diagnosis and a means of monitoring therapeutic efficacy, both of which may be supported by the use of GBA-targeting activity-based probes (ABPs). Here, we report the synthesis and structural analysis of a range of cyclophellitol epoxide and aziridine inhibitors and ABPs for GBA. We demonstrate their covalent mechanism-based mode of action and uncover binding of the new N-functionalised aziridines to the ligand binding cleft. These inhibitors became scaffolds for the development of ABPs; the O6-fluorescent tags of which bind in an allosteric site at the dimer interface. Considering GBA's preference for O6- and N-functionalised reagents, a bi-functional aziridine ABP was synthesized as a potentially more powerful imaging agent. Whilst this ABP binds to two unique active site clefts of GBA, no further benefit in potency was achieved over our first generation ABPs. Nevertheless, such ABPs should serve useful in the study of GBA in relation to GD and inform the design of future probes.

PubMed: 34570911
DOI: 10.1002/chem.202102359

実験手法

X-RAY DIFFRACTION (1.7 Å)