Three dimensional structure of a bacterial α-l-fucosidase with a 5-membered iminocyclitol inhibitor.

Abstract

Fucosidases, enzymes that cleave fucose from the non-reducing end of a glycan, represent promising medicinal targets reflecting their roles in cancer metastasis, inflammation, host-parasite interactions and the lysosomal storage disorder fucosidosis. The X-ray crystal structures of Bacteroides thetaiotaomicron GH29 α-l-fucosidase (BtFuc2970) in a new crystal form (at a resolution of 1.59Å) and liganded with a 5-membered iminocyclitol inhibitor (1.73Å) are reported herein. The 5-membered iminocyclitol binds in a (3)E conformation, mimicking the proposed (3)H4 half chair transition-state of the enzyme catalysed reaction, and its Ki for BtFuc2970 was determined as 2μM. Structural analysis of fucosidase inhibition through 5-membered iminocyclitols will aid in the rational design of more potent fucosidase inhibitors for treatment of a range of medical conditions.

• Authors: Daniel W Wright, Antonio J Moreno-Vargas, Ana T Carmona, Inmaculada Robina, Gideon J Davies
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 21 Issue 16 Pg. 4751-4 (Aug 15 2013) ISSN: 1464-3391 [Electronic] England
• PMID: 23830696 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• 2-(1H-benzo(d)imidazol-2-yl)-5-methylpyrrolidine-3,4-diol
• Benzimidazoles
• Enzyme Inhibitors
• Pyrrolidines
• Recombinant Proteins
• alpha-L-Fucosidase

Topics

• Bacteroides (enzymology)
• Benzimidazoles (chemical synthesis, chemistry)
• Binding Sites
• Catalytic Domain
• Crystallography, X-Ray
• Drug Design
• Enzyme Inhibitors (chemistry, metabolism)
• Kinetics
• Molecular Conformation
• Protein Binding
• Pyrrolidines (chemical synthesis, chemistry)
• Recombinant Proteins (biosynthesis, chemistry, genetics)
• alpha-L-Fucosidase (antagonists & inhibitors, genetics, metabolism)