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

D.W. Wright; A.J. Moreno-Vargas; A.T. Carmona; I. Robina; G.J. Davies

doi:10.1016/j.bmc.2013.05.056

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

D.W. Wright, A.J. Moreno-Vargas, A.T. Carmona, I. Robina, G.J. Davies

Chemistry

Research output: Contribution to journal › Article › peer-review

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 1.59 Å) and liganded with a 5-membered iminocyclitol inhibitor (1.73 Å) are reported herein. The 5-membered iminocyclitol binds in a E conformation, mimicking the proposed H half chair transition-state of the enzyme catalysed reaction, and its K 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.

Original language	English
Pages (from-to)	4751-4754
Journal	Bioorganic & Medicinal Chemistry
Volume	21
Issue number	16
DOIs	https://doi.org/10.1016/j.bmc.2013.05.056
Publication status	Published - 15 Aug 2013

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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 1.59 {\AA}) and liganded with a 5-membered iminocyclitol inhibitor (1.73 {\AA}) are reported herein. The 5-membered iminocyclitol binds in a E conformation, mimicking the proposed H half chair transition-state of the enzyme catalysed reaction, and its K 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.",

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T1 - Three dimensional structure of a bacterial α-l-fucosidase with a 5-membered iminocyclitol inhibitor

AU - Wright, D.W.

AU - Moreno-Vargas, A.J.

AU - Carmona, A.T.

AU - Robina, I.

AU - Davies, G.J.

PY - 2013/8/15

Y1 - 2013/8/15

N2 - 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 E conformation, mimicking the proposed H half chair transition-state of the enzyme catalysed reaction, and its K 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.

AB - 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 E conformation, mimicking the proposed H half chair transition-state of the enzyme catalysed reaction, and its K 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.

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JO - Bioorganic & Medicinal Chemistry

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IS - 16

ER -

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

Abstract

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