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PDBsum entry 6bpp
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Lipid transport
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PDB id
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6bpp
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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 for dual-Mode inhibition of the abc transporter msba.
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Authors
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H.Ho,
A.Miu,
M.K.Alexander,
N.K.Garcia,
A.Oh,
I.Zilberleyb,
M.Reichelt,
C.D.Austin,
C.Tam,
S.Shriver,
H.Hu,
S.S.Labadie,
J.Liang,
L.Wang,
J.Wang,
Y.Lu,
H.E.Purkey,
J.Quinn,
Y.Franke,
K.Clark,
M.H.Beresini,
M.W.Tan,
B.D.Sellers,
T.Maurer,
M.F.T.Koehler,
A.T.Wecksler,
J.R.Kiefer,
V.Verma,
Y.Xu,
M.Nishiyama,
J.Payandeh,
C.M.Koth.
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Ref.
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Nature, 2018,
557,
196-201.
[DOI no: ]
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PubMed id
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Abstract
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The movement of core-lipopolysaccharide across the inner membrane of
Gram-negative bacteria is catalysed by an essential ATP-binding cassette
transporter, MsbA. Recent structures of MsbA and related transporters have
provided insights into the molecular basis of active lipid transport; however,
structural information about their pharmacological modulation remains limited.
Here we report the 2.9 Å resolution structure of MsbA in complex with G907, a
selective small-molecule antagonist with bactericidal activity, revealing an
unprecedented mechanism of ABC transporter inhibition. G907 traps MsbA in an
inward-facing, lipopolysaccharide-bound conformation by wedging into an
architecturally conserved transmembrane pocket. A second allosteric mechanism of
antagonism occurs through structural and functional uncoupling of the
nucleotide-binding domains. This study establishes a framework for the selective
modulation of ABC transporters and provides rational avenues for the design of
new antibiotics and other therapeutics targeting this protein family.
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