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PDBsum entry 6b8b
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Lipid transport/activator
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PDB id
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6b8b
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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 antibiotic novobiocin binds and activates the atpase that powers lipopolysaccharide transport.
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Authors
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J.M.May,
T.W.Owens,
M.D.Mandler,
B.W.Simpson,
M.B.Lazarus,
D.J.Sherman,
R.M.Davis,
S.Okuda,
W.Massefski,
N.Ruiz,
D.Kahne.
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Ref.
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J Am Chem Soc, 2017,
139,
17221-17224.
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PubMed id
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Abstract
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Novobiocin is an orally active antibiotic that inhibits DNA gyrase by binding
the ATP-binding site in the ATPase subunit. Although effective against
Gram-positive pathogens, novobiocin has limited activity against Gram-negative
organisms due to the presence of the lipopolysaccharide-containing outer
membrane, which acts as a permeability barrier. Using a novobiocin-sensitive
Escherichia coli strain with a leaky outer membrane, we identified a mutant with
increased resistance to novobiocin. Unexpectedly, the mutation that increases
novobiocin resistance was not found to alter gyrase, but the ATPase that powers
lipopolysaccharide (LPS) transport. Co-crystal structures, biochemical, and
genetic evidence show novobiocin directly binds this ATPase. Novobiocin does not
bind the ATP binding site but rather the interface between the ATPase subunits
and the transmembrane subunits of the LPS transporter. This interaction
increases the activity of the LPS transporter, which in turn alters the
permeability of the outer membrane. We propose that novobiocin will be a useful
tool for understanding how ATP hydrolysis is coupled to LPS transport.
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