3cv5 Citations

Golgi alpha-mannosidase II cleaves two sugars sequentially in the same catalytic site.

Proc Natl Acad Sci U S A 105 9570-5 (2008)
Related entries: 3czn, 3czs

Cited: 54 times
EuropePMC logo PMID: 18599462

Abstract

Golgi alpha-mannosidase II (GMII) is a key glycosyl hydrolase in the N-linked 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.

Articles - 3cv5 mentioned but not cited (1)

  1. Human lysosomal alpha-mannosidases exhibit different inhibition and metal binding properties. Venkatesan M, Kuntz DA, Rose DR. Protein Sci 18 2242-2251 (2009)


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