Combined inhibitor free-energy landscape and structural analysis reports on the mannosidase conformational coordinate

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, in...

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Hauptverfasser: Williams, Rohan J, Iglesias-Fernández, Javier, Stepper, Judith, Jackson, Adam, Thompson, Andrew J, Lowe, Elisabeth C, White, Jonathan M, Gilbert, Harry J, Rovira, Carme, Davies, Gideon J, Williams, Spencer J
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Sprache:eng
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Zusammenfassung: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.
DOI:10.1002/anie.201308334