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

DOI: 10.1016/j.bmc.2013.05.056 DOI Help
PMID: 23830696 PMID Help

Authors: Daniel W. Wright (University of York) , Antonio J. Moreno-vargas (University of Seville) , Ana T. Carmona (University of Seville) , Inmaculada Robina (University of Seville) , Gideon J. Davies (University of York)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry , VOL 21 (16) , PAGES 4751 - 4754

State: Published (Approved)
Published: June 2013

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 ?-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 ?M. 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.

Journal Keywords: Benzimidazoles; Binding; Catalytic; Crystallography; X-Ray; Drug; Enzyme; Kinetics; Molecular; Protein; Pyrrolidines; Recombinant; alpha-L-Fucosidase

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I03-Macromolecular Crystallography

Other Facilities: ESRF

Added On: 30/09/2013 15:31

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