title: The molecular basis of inhibition of Golgi alpha-mannosidase II by mannostatin A.
abstract: Mannostatin A is a potent inhibitor of the mannose-trimming enzyme, Golgi alpha-mannosidase II (GMII), which acts late in the N-glycan processing pathway. Inhibition of this enzyme provides a route to blocking the transformation-associated changes in cancer cell surface oligosaccharide structures. Here, we report on the synthesis of new Mannostatin derivatives and analyze their binding in the active site of Drosophila GMII by X-ray crystallography. The results indicate that the interaction with the backbone carbonyl of Arg876 is crucial to the high potency of the inhibitor-an effect enhanced by the hydrophobic interaction between the thiomethyl group and an aromatic pocket vicinal to the cleavage site. The various structures indicate that differences in the hydration of protein-ligand complexes are also important determinants of plasticity as well as selectivity of inhibitor binding.
authors.affiliation: Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Kuntz
authors.forename: Wei
authors.initials: W
authors.lastname: Zhong
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.forename: David R
authors.initials: DR
authors.lastname: Rose
authors.forename: Geert-Jan
authors.initials: GJ
authors.lastname: Boons
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D003517:Cyclopentanes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004331:Drosophila melanogaster / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D057927:Hydrophobic and Hydrophilic Interactions; D008361:Mannosidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity; D013455:Sulfur / Q000737:chemistry
chemical_list: D003517:Cyclopentanes; D004791:Enzyme Inhibitors; C060107:mannostatin A; D013455:Sulfur; D008361:Mannosidases; C038829:mannosyl-oligosaccharide 1,3 - 1,6-alpha-mannosidase