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PDBsum entry 1pcw
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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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Structure-Based design of novel inhibitors of 3-Deoxy-D-Manno-Octulosonate 8-Phosphate synthase.
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Authors
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X.Xu,
J.Wang,
C.Grison,
S.Petek,
P.Coutrot,
M.R.Birck,
R.W.Woodard,
D.L.Gatti.
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Ref.
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Drug Des Discov, 2003,
18,
91-99.
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PubMed id
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Abstract
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3-Deoxy-D-manno-octulosonate 8-phosphate (KDO8P) is the phosphorylated precursor
of KDO, an essential sugar of the lipopolysaccharide of Gram negative bacteria.
KDO8P is produced by a specific synthase (KDO8PS) by condensing arabinose
5-phosphate (A5P) and phosphoenolpyruvate (PEP), with release of inorganic
phosphate. As KDO8PS is present in bacteria and plants, but not in mammalian
cells, and mutations that inactivate KDO8PS also block cell replication, KDO8PS
is a promising target for the design of new antimicrobials that act by blocking
lipopolysaccharide biosynthesis. Previous studies have shown that a compound
mimicking an intermediate of the condensation reaction is a good ligand and a
powerful inhibitor. Here we report on the crystallographic investigation of the
binding to KDO8PS of new derivatives of this original inhibitor. The structures
of the enzyme in complex with these compounds, and also with the PEP analogs,
2-phosphoglyceric acid (2-PGA) and Z-methyl-PEP, point to future strategies for
the design of novel inhibitors of KDO8PS.
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