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PDBsum entry 3p3c
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References listed in PDB file
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Key reference
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Title
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Species-Specific and inhibitor-Dependent conformations of lpxc: implications for antibiotic design.
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Authors
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C.J.Lee,
X.Liang,
X.Chen,
D.Zeng,
S.H.Joo,
H.S.Chung,
A.W.Barb,
S.M.Swanson,
R.A.Nicholas,
Y.Li,
E.J.Toone,
C.R.Raetz,
P.Zhou.
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Ref.
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Chem Biol, 2011,
18,
38-47.
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PubMed id
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Abstract
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LpxC is an essential enzyme in the lipid A biosynthetic pathway in gram-negative
bacteria. Several promising antimicrobial lead compounds targeting LpxC have
been reported, though they typically display a large variation in potency
against different gram-negative pathogens. We report that inhibitors with a
diacetylene scaffold effectively overcome the resistance caused by sequence
variation in the LpxC substrate-binding passage. Compound binding is captured in
complex with representative LpxC orthologs, and structural analysis reveals
large conformational differences that mostly reflect inherent molecular features
of distinct LpxC orthologs, whereas ligand-induced structural adaptations occur
at a smaller scale. These observations highlight the need for a molecular
understanding of inherent structural features and conformational plasticity of
LpxC enzymes for optimizing LpxC inhibitors as broad-spectrum antibiotics
against gram-negative infections.
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