Published in
Wiley, Angewandte Chemie International Edition, 4(53), p. 1087-1091, 2013
Wiley, Angewandte Chemie, 4(126), p. 1105-1109, 2013
Links
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- [www.ncbi.nlm.nih.gov] | PDF
- [eprints.whiterose.ac.uk]
- [eprints.whiterose.ac.uk] | PDF
- [diposit.ub.edu] | PDF
- [europepmc.org] | PDF
- [www.researchgate.net] | PDF
- [www.ncbi.nlm.nih.gov] | PDF
Tools
Combined Inhibitor Free-Energy Landscape and Structural Analysis Reports on the Mannosidase Conformational Coordinate**
,
Elisabeth C. Lowe,
Jonathan M. White,
Harry J. Gilbert,
Carme Rovira ,
Gideon J. Davies,
Gideon J. Davies*,
Spencer J. Williams
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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.