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

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 1.59 Å) and liganded with a 5-membered iminocyclitol inhibitor (1.73 Å) 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 2 μM. 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.