6Z3I

Structure of recombinant beta-glucocerebrosidase in complex with bifunctional cyclophellitol aziridine activity based probe

This is a non-PDB format compatible entry.

Summary for 6Z3I

• Entry DOI: 10.2210/pdb6z3i/pdb
• Related: 6YTP 6YTR 6YUT 6YV3 6Z39
• Descriptor: 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, SULFATE ION, ... (7 entities in total)
• Functional Keywords: hydrolase, lysosomal hydrolase, activity based probe
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 58611.14

Authors

Rowland, R.J.,Davies, G.J. (deposition date: 2020-05-20, release date: 2021-06-30, Last modification date: 2024-11-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.8 Å)