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PDBsum entry 1q0h
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Oxidoreductase
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PDB id
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1q0h
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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The crystal structure of e.Coli 1-Deoxy-D-Xylulose-5-Phosphate reductoisomerase in a ternary complex with the antimalarial compound fosmidomycin and NADPH reveals a tight-Binding closed enzyme conformation.
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Authors
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A.Mac sweeney,
R.Lange,
R.P.Fernandes,
H.Schulz,
G.E.Dale,
A.Douangamath,
P.J.Proteau,
C.Oefner.
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Ref.
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J Mol Biol, 2005,
345,
115-127.
[DOI no: ]
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PubMed id
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Abstract
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The key enzyme in the non-mevalonate pathway of isoprenoid biosynthesis,
1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) has been shown to be the
target enzyme of fosmidomycin, an antimalarial, antibacterial and herbicidal
compound. Here we report the crystal structure of selenomethionine-labelled
Escherichia coli DXR in a ternary complex with NADPH and fosmidomycin at 2.2 A
resolution. The structure reveals a considerable conformational rearrangement
upon fosmidomycin binding and provides insights into the slow, tight binding
inhibition mode of the inhibitor. Although the inhibitor displays an unusual
non-metal mediated mode of inhibition, which is an artefact most likely due to
the low metal affinity of DXR at the pH used for crystallization, the structural
data add valuable information for the rational design of novel DXR inhibitors.
Using this structure together with the published structural data and the 1.9 A
crystal structure of DXR in a ternary complex with NADPH and the substrate
1-deoxy-D-xylulose 5-phosphate, a model for the physiologically relevant
tight-binding mode of inhibition is proposed. The structure of the substrate
complex must be interpreted with caution due to the presence of a second
diastereomer in the active site.
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Figure 6.
Figure 6. (A) An FoKFc omit electron density map of fosmidomycin in the active site of DXR, contoured at 3s. Met276
is shown in orange on the left and Met214 is shown in two conformations: that of SeMet214 in magenta (right) and that of
wild-type Met214 in orange (left). (B) Hydrogen bonding interactions of the inhibitor fosmidomycin in the active site of
DXR. (C) A schematic diagram of fosmidomycin binding to SeMet-labelled DXR.
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Figure 7.
Figure 7. (A) An FoKFc omit electron density map of the substrate DXP in the active site of DXR, contoured at 3s. The
position of the hydroxyl group in the L-configuration at C4 is depicted in green. (B) Hydrogen bonding interactions of
the substrate DXP in the active site of DXR. The position of the hydroxyl group in the L-configuration at C4 is depicted in
green. (C) A schematic diagram of the substrate DXP binding to DXR. For clarity, the bond between the carboxylate of
E231 and the hydroxyl group of C4 of DXP has been omitted.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2005,
345,
115-127)
copyright 2005.
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