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Revealing the Mechanism for Covalent Inhibition of Glycoside Hydrolases by Carbasugars at an Atomic Level

Resource type
Date created
2018-08-13
Abstract
Mechanism-based glycoside hydrolase inhibitors are carbohydrate analogs that mimic the natural substrate’s structure. Their covalent bond formation with the glycoside hydrolase makes these compounds excellent tools for chemical biology and potential drug candidates. Here we report the synthesis of cyclohexene-based α-galactopyranoside mimics and the kinetic and structural characterization of their inhibitory activity toward an α-galactosidase from Thermotoga maritima (TmGalA). By solving the structures of several enzyme-bound species during mechanism-based covalent inhibition of TmGalA, we show that the Michaelis complexes for intact inhibitor and product have half-chair (2H3) conformations for the cyclohexene fragment, while the covalently linked intermediate adopts a flattened half-chair (2H3) conformation. Hybrid QM/MM calculations confirm the structural and electronic properties of the enzyme-bound species and provide insight into key interactions in the enzyme-active site. These insights should stimulate the design of mechanism-based glycoside hydrolase inhibitors with tailored chemical properties.
Document
Description
The full text of this paper will be available in [Sept, 2020] due to the embargo policies of Nature Communications for works funded by Natural Sciences and Engineering Research Council of Canada (NSERC). Contact summit@sfu.ca to enquire if the full text of the accepted manuscript can be made available to you.”
Published as
Nature Communications, volume 9, Article number: 3243 (2018). DOI: https://doi.org/10.1038/s41467-018-05702-7
Publication title
Nature Communications
Document title
Revealing the Mechanism for Covalent Inhibition of Glycoside Hydrolases by Carbasugars at an Atomic Level
Date
2018
Volume
9
Copyright statement
Copyright is held by the author(s).
Scholarly level
Peer reviewed?
Yes
Language
English
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