title: 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.affiliation: Structural Biology Laboratory, Department of Chemistry, University of York, York YO10 5DD, United Kingdom.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Wright
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Moreno-Vargas
authors.forename: Ana T
authors.initials: AT
authors.lastname: Carmona
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Robina
authors.forename: Gideon J
authors.initials: GJ
authors.lastname: Davies
mesh_terms: D001439:Bacteroides / Q000201:enzymology; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry*; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008968:Molecular Conformation; D011485:Protein Binding; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D005644:alpha-L-Fucosidase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C586292:2-(1H-benzo(d)imidazol-2-yl)-5-methylpyrrolidine-3,4-diol; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D011994:Recombinant Proteins; D005644:alpha-L-Fucosidase
keywords: Carbohydrate; Conformational analysis; Enzyme inhibition; Glycobiology; Glycosidase