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PDBsum entry 4u3c
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References listed in PDB file
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Key reference
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Title
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Crystal structures of mycobacterium tuberculosis glge and complexes with non-Covalent inhibitors.
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Authors
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J.J.Lindenberger,
S.K.Veleti,
B.N.Wilson,
S.J.Sucheck,
D.R.Ronning.
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Ref.
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Sci Rep, 2015,
5,
12830.
[DOI no: ]
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PubMed id
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Note: In the PDB file this reference is
annotated as "TO BE PUBLISHED". The citation details given above have
been manually determined.
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Abstract
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GlgE is a bacterial maltosyltransferase that catalyzes the elongation of a
cytosolic, branched α-glucan. In Mycobacterium tuberculosis (M. tb),
inactivation of GlgE (Mtb GlgE) results in the rapid death of the organism due
to a toxic accumulation of the maltosyl donor, maltose-1-phosphate (M1P),
suggesting that GlgE is an intriguing target for inhibitor design. In this
study, the crystal structures of the Mtb GlgE in a binary complex with maltose
and a ternary complex with maltose and a maltosyl-acceptor molecule,
maltohexaose, were solved to 3.3 Å and 4.0 Å, respectively. The
maltohexaose structure reveals a dominant site for α-glucan binding. To obtain
more detailed interactions between first generation, non-covalent inhibitors and
GlgE, a variant Streptomyces coelicolor GlgEI (Sco GlgEI-V279S) was made to
better emulate the Mtb GlgE M1P binding site. The structure of Sco GlgEI-V279S
complexed with α-maltose-C-phosphonate (MCP), a non-hydrolyzable substrate
analogue, was solved to 1.9 Å resolution, and the structure of Sco
GlgEI-V279S complexed with
2,5-dideoxy-3-O-α-D-glucopyranosyl-2,5-imino-D-mannitol (DDGIM), an
oxocarbenium mimic, was solved to 2.5 Å resolution. These structures detail
important interactions that contribute to the inhibitory activity of these
compounds, and provide information on future designs that may be exploited to
improve upon these first generation GlgE inhibitors.
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