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PDBsum entry 5ens
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Transport protein
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PDB id
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5ens
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References listed in PDB file
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Key reference
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Title
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Molecular basis for inhibition of acrb multidrug efflux pump by novel and powerful pyranopyridine derivatives.
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Authors
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H.Sjuts,
A.V.Vargiu,
S.M.Kwasny,
S.T.Nguyen,
H.S.Kim,
X.Ding,
A.R.Ornik,
P.Ruggerone,
T.L.Bowlin,
H.Nikaido,
K.M.Pos,
T.J.Opperman.
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Ref.
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Proc Natl Acad Sci U S A, 2016,
113,
3509-3514.
[DOI no: ]
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PubMed id
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Abstract
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TheEscherichia coliAcrAB-TolC efflux pump is the archetype of the resistance
nodulation cell division (RND) exporters from Gram-negative bacteria.
Overexpression of RND-type efflux pumps is a major factor in multidrug
resistance (MDR), which makes these pumps important antibacterial drug discovery
targets. We have recently developed novel pyranopyridine-based inhibitors of
AcrB, which are orders of magnitude more powerful than the previously known
inhibitors. However, further development of such inhibitors has been hindered by
the lack of structural information for rational drug design. Although only the
soluble, periplasmic part of AcrB binds and exports the ligands, the presence of
the membrane-embedded domain in AcrB and its polyspecific binding behavior have
made cocrystallization with drugs challenging. To overcome this obstacle, we
have engineered and produced a soluble version of AcrB [AcrB periplasmic domain
(AcrBper)], which is highly congruent in structure with the periplasmic part of
the full-length protein, and is capable of binding substrates and potent
inhibitors. Here, we describe the molecular basis for pyranopyridine-based
inhibition of AcrB using a combination of cellular, X-ray crystallographic, and
molecular dynamics (MD) simulations studies. The pyranopyridines bind within a
phenylalanine-rich cage that branches from the deep binding pocket of AcrB,
where they form extensive hydrophobic interactions. Moreover, the increasing
potency of improved inhibitors correlates with the formation of a delicate
protein- and water-mediated hydrogen bond network. These detailed insights
provide a molecular platform for the development of novel combinational
therapies using efflux pump inhibitors for combating multidrug resistant
Gram-negative pathogens.
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