Williams, Rohan J, Iglesias-Fernández, Javier, Stepper, Judith orcid.org/0000-0003-3201-8099 et al. (8 more authors) (2014) Combined inhibitor free-energy landscape and structural analysis reports on the mannosidase conformational coordinate. Angewandte Chemie International Edition. pp. 1087-1091. ISSN 1433-7851
Abstract
Mannosidases catalyze the hydrolysis of a diverse range of polysaccharides and glycoconjugates, and the various sequence-based mannosidase families have evolved ingenious strategies to overcome the stereoelectronic challenges of mannoside chemistry. Using a combination of computational chemistry, inhibitor design and synthesis, and X-ray crystallography of inhibitor/enzyme complexes, it is demonstrated that mannoimidazole-type inhibitors are energetically poised to report faithfully on mannosidase transition-state conformation, and provide direct evidence for the conformational itinerary used by diverse mannosidases, including β-mannanases from families GH26 and GH113. Isofagomine-type inhibitors are poor mimics of transition-state conformation, owing to the high energy barriers that must be crossed to attain mechanistically relevant conformations, however, these sugar-shaped heterocycles allow the acquisition of ternary complexes that span the active site, thus providing valuable insight into active-site residues involved in substrate recognition.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Chemistry (York) |
Funding Information: | Funder Grant number BBSRC (BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL) BB/G016127/1 |
Depositing User: | Pure (York) |
Date Deposited: | 26 Feb 2015 14:28 |
Last Modified: | 16 Oct 2024 12:22 |
Published Version: | https://doi.org/10.1002/anie.201308334 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1002/anie.201308334 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:83836 |
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Filename: 1087_ftp.pdf
Description: Combined Inhibitor Free-Energy Landscape and Structural Analysis Reports on the Mannosidase Conformational Coordinate