title: Dissecting conformational contributions to glycosidase catalysis and inhibition.
abstract: Glycoside hydrolases (GHs) are classified into >100 sequence-based families. These enzymes process a wide variety of complex carbohydrates with varying stereochemistry at the anomeric and other ring positions. The shapes that these sugars adopt upon binding to their cognate GHs, and the conformational changes that occur along the catalysis reaction coordinate is termed the conformational itinerary. Efforts to define the conformational itineraries of GHs have focussed upon the critical points of the reaction: substrate-bound (Michaelis), transition state, intermediate (if relevant) and product-bound. Recent approaches to defining conformational itineraries that marry X-ray crystallography of enzymes bound to ligands that mimic the critical points, along with advanced computational methods and kinetic isotope effects are discussed.
authors.affiliation: School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Speciale
authors.affiliation: Department of Chemistry, University of York, Heslington, York YO10 5DD, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Thompson
authors.affiliation: Department of Chemistry, University of York, Heslington, York YO10 5DD, United Kingdom.
authors.forename: Gideon J
authors.initials: GJ
authors.lastname: Davies
authors.affiliation: School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address: sjwill@unimelb.edu.au.
authors.forename: Spencer J
authors.initials: SJ
authors.lastname: Williams
mesh_terms: D002241:Carbohydrates / Q000737:chemistry; D002384:Catalysis; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D008358:Mannose / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D002241:Carbohydrates; D004791:Enzyme Inhibitors; D006026:Glycoside Hydrolases; D009439:Neuraminidase; D008358:Mannose