title: Combined inhibitor free-energy landscape and structural analysis reports on the mannosidase conformational coordinate.
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.
authors: School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Vic 3010 (Australia).
authors: Rohan J
authors: RJ
authors: Williams
authors: Javier
authors: J
authors: Iglesias-Fernández
authors: Judith
authors: J
authors: Stepper
authors: Adam
authors: A
authors: Jackson
authors: Andrew J
authors: AJ
authors: Thompson
authors: Elisabeth C
authors: EC
authors: Lowe
authors: Jonathan M
authors: JM
authors: White
authors: Harry J
authors: HJ
authors: Gilbert
authors: Carme
authors: C
authors: Rovira
authors: Gideon J
authors: GJ
authors: Davies
authors: Spencer J
authors: SJ
authors: Williams
mesh_terms: D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D050112:Imino Pyranoses / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008361:Mannosidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D050112:Imino Pyranoses; C098432:isofagomine; D008361:Mannosidases
keywords: computational chemistry; conformation analysis; enzymes; inhibitors; transition states