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

• Published in: Bioorganic & medicinal chemistry Vol. 21; no. 16; pp. 4751 - 4754
• Main Authors: Wright, Daniel W., Moreno-Vargas, Antonio J., Carmona, Ana T., Robina, Inmaculada, Davies, Gideon J.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.08.2013
• Subjects: alpha-L-fucosidase; alpha-L-Fucosidase - antagonists & inhibitors; alpha-L-Fucosidase - genetics; alpha-L-Fucosidase - metabolism; Bacteroides - enzymology; Bacteroides thetaiotaomicron; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Binding Sites; Carbohydrate; Catalytic Domain; chemistry; Conformational analysis; Crystallography, X-Ray; Drug Design; Enzyme inhibition; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; fucose; Glycobiology; Glycosidase; host-parasite relationships; inflammation; Kinetics; metastasis; Molecular Conformation; Protein Binding; Pyrrolidines - chemical synthesis; Pyrrolidines - chemistry; Recombinant Proteins - biosynthesis; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; X-ray diffraction; Enzyme inhibition; Glycosidase; Carbohydrate; Glycobiology; Conformational analysis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2013.05.056

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 3E conformation, mimicking the proposed 3H4 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.