Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 28, Pages 9570-9575Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0802206105
Keywords
cancer therapy; enzyme mechanism; N-glycosylation pathway; x-ray crystallography; glycoside hydrolase
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Golgi alpha-mannosidase II (GMII) is a key glycosyl hydrolase in the Winked glycosylation pathway. it catalyzes the removal of two different mannosyl linkages of GlcNAcMan(5)GlcNAc(2), which is the committed step in complex N-glycan synthesis. inhibition of this enzyme has shown promise in certain cancers in both laboratory and clinical settings. Here we present the high-resolution crystal structure of a nucleophile mutant of Drosophila melanogaster GMII (dGMII) bound to its natural oligosaccharide substrate and an oligosaccharide precursor as well as the structure of the unliganded mutant. These structures allow us to identify three sugar-binding subsites within the larger active site cleft. Our results allow for the formulation of the complete catalytic process of dGMII, which involves a specific order of bond cleavage, and a major substrate rearrangement in the active site. This process is likely conserved for all GMII enzymes-but not in the structurally related lysosomal mannosidase-and will form the basis for the design of specific inhibitors against GMII.
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