title: Structural Snapshots for Mechanism-Based Inactivation of a Glycoside Hydrolase by Cyclopropyl Carbasugars.
abstract: Glycoside hydrolases (GHs) have attracted considerable attention as targets for therapeutic agents, and thus mechanism-based inhibitors are of great interest. We report the first structural analysis of a carbocyclic mechanism-based GH inactivator, the results of which show that the two Michaelis complexes are in2H3conformations. We also report the synthesis and reactivity of a fluorinated analogue and the structure of its covalently linked intermediate (flattened2H3half-chair). We conclude that these inactivator reactions mainly involve motion of the pseudo-anomeric carbon atom, knowledge that should stimulate the design of new transition-state analogues for use as chemical biology tools.
authors: Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
authors: Christopher
authors: C
authors: Adamson
authors: Biomedical Sciences Research Complex, University of St Andrews, North Haugh, St Andrews, Fife, UK.
authors: Robert J
authors: RJ
authors: Pengelly
authors: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
authors: Saeideh
authors: S
authors: Shamsi Kazem Abadi
authors: Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
authors: Saswati
authors: S
authors: Chakladar
authors: Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
authors: Jason
authors: J
authors: Draper
authors: Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
authors: Robert
authors: R
authors: Britton
authors: Biomedical Sciences Research Complex, University of St Andrews, North Haugh, St Andrews, Fife, UK.
authors: Tracey M
authors: TM
authors: Gloster
authors: Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
authors: Andrew J
authors: 0000-0002-8378-6752
authors: AJ
authors: Bennet
keywords: X-ray crystallography; carbocycles; enzyme mechanisms; glycoside hydrolases; inhibitors