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Combined Inhibitor Free-Energy Landscape and Structural Analysis Reports on the Mannosidase Conformational Coordinate

DOI: 10.1002/anie.201308334 DOI Help
PMID: 24339341 PMID Help

Authors: Rohan J. Williams (University of Melbourne) , Javier Iglesias-fernández (Universitat de Barcelona) , Judith Stepper (University of York) , Adam Jackson (Newcastle University) , Andrew Thompson (University of York) , Elisabeth C. Lowe (Newcastle University) , John White (University of Melbourne) , Harry J. Gilbert (Newcastle University) , Carme Rovira (Universitat de Barcelona) , Gideon J. Davies (University of York) , Spencer J. Williams (University of Melbourne)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Angewandte Chemie International Edition , VOL 53 (4) , PAGES 1087 - 1091

State: Published (Approved)
Published: January 2014
Diamond Proposal Number(s): 7864

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 ╬▓-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.

Journal Keywords: X-Ray; Enzyme; Imidazoles; Imino; Mannosidases; Models; Molecular; Structure-Activity; Thermodynamics

Subject Areas: Chemistry, Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography