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PDBsum entry 3d4z
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References listed in PDB file
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Key reference
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Title
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Structural analysis of golgi alpha-Mannosidase ii inhibitors identified from a focused glycosidase inhibitor screen.
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Authors
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D.A.Kuntz,
C.A.Tarling,
S.G.Withers,
D.R.Rose.
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Ref.
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Biochemistry, 2008,
47,
10058-10068.
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PubMed id
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Abstract
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The N-glycosylation pathway is a target for pharmaceutical intervention in a
number of pathological conditions including cancer. Golgi alpha-mannosidase II
(GMII) is the final glycoside hydrolase in the pathway and has been the target
for a number of synthetic efforts aimed at providing more selective and
effective inhibitors. Drosophila GMII (dGMII) has been extensively studied due
to the ease of obtaining high resolution structural data, allowing the
observation of substrate distortion upon binding and after formation of a
trapped covalent reaction intermediate. However, attempts to find new inhibitor
leads by high-throughput screening of large commercial libraries or through in
silico docking were unsuccessful. In this paper we provide a kinetic and
structural analysis of five inhibitors derived from a small glycosidase-focused
library. Surprisingly, four of these were known inhibitors of beta-glucosidases.
X-ray crystallographic analysis of the dGMII:inhibitor complexes highlights the
ability of the zinc-containing GMII active site to deform compounds, even ones
designed as conformationally restricted transition-state mimics of
beta-glucosidases, into binding entities that have inhibitory activity. Although
these deformed conformations do not appear to be on the expected conformational
itinerary of the enzyme, and are thus not transition-state mimics of GMII, they
allow positioning of the three vicinal hydroxyls of the bound gluco-inhibitors
into similar locations to those found with mannose-containing substrates,
underlining the importance of these hydrogen bonds for binding. Further, these
studies show the utility of targeting the acid-base catalyst using appropriately
positioned positively charged nitrogen atoms, as well as the challenges
associated with aglycon substitutions.
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