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PDBsum entry 4mqy
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Hydrolase/hydrolase inhibitor
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PDB id
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4mqy
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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 basis of the promiscuous inhibitor susceptibility of escherichia coli lpxc.
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Authors
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C.J.Lee,
X.Liang,
R.Gopalaswamy,
J.Najeeb,
E.D.Ark,
E.J.Toone,
P.Zhou.
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Ref.
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Acs Chem Biol, 2014,
9,
237-246.
[DOI no: ]
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PubMed id
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Abstract
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The LpxC enzyme in the lipid A biosynthetic pathway is one of the most promising
and clinically unexploited antibiotic targets for treatment of
multidrug-resistant Gram-negative infections. Progress in medicinal chemistry
has led to the discovery of potent LpxC inhibitors with a variety of chemical
scaffolds and distinct antibiotic profiles. The vast majority of these
compounds, including the nanomolar inhibitors L-161,240 and BB-78485, are highly
effective in suppressing the activity of Escherichia coli LpxC (EcLpxC) but not
divergent orthologs such as Pseudomonas aeruginosa LpxC (PaLpxC) in vitro. The
molecular basis for such promiscuous inhibition of EcLpxC has remained poorly
understood. Here, we report the crystal structure of EcLpxC bound to L-161,240,
providing the first molecular insight into L-161,240 inhibition. Additionally,
structural analysis of the EcLpxC/L-161,240 complex together with the
EcLpxC/BB-78485 complex reveals an unexpected backbone flipping of the Insert I
βa-βb loop in EcLpxC in comparison with previously reported crystal structures
of EcLpxC complexes with l-threonyl-hydroxamate-based broad-spectrum inhibitors.
Such a conformational switch, which has only been observed in EcLpxC but not in
divergent orthologs such as PaLpxC, results in expansion of the active site of
EcLpxC, enabling it to accommodate LpxC inhibitors with a variety of head
groups, including compounds containing single (R- or S-enantiomers) or double
substitutions at the neighboring Cα atom of the hydroxamate warhead group.
These results highlight the importance of understanding inherent conformational
plasticity of target proteins in lead optimization.
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