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PDBsum entry 2m6x
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Membrane protein
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PDB id
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2m6x
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References listed in PDB file
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Key reference
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Title
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Unusual architecture of the p7 channel from hepatitis c virus.
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Authors
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B.Ouyang,
S.Xie,
M.J.Berardi,
X.Zhao,
J.Dev,
W.Yu,
B.Sun,
J.J.Chou.
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Ref.
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Nature, 2013,
498,
521-525.
[DOI no: ]
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PubMed id
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Abstract
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The hepatitis C virus (HCV) has developed a small membrane protein, p7, which
remarkably can self-assemble into a large channel complex that selectively
conducts cations. We wanted to examine the structural solution that the
viroporin adopts in order to achieve selective cation conduction, because p7 has
no homology with any of the known prokaryotic or eukaryotic channel proteins.
The activity of p7 can be inhibited by amantadine and rimantadine, which are
potent blockers of the influenza M2 channel and licensed drugs against influenza
infections. The adamantane derivatives have been used in HCV clinical trials,
but large variation in drug efficacy among the various HCV genotypes has been
difficult to explain without detailed molecular structures. Here we determine
the structures of this HCV viroporin as well as its drug-binding site using the
latest nuclear magnetic resonance (NMR) technologies. The structure exhibits an
unusual mode of hexameric assembly, where the individual p7 monomers, i, not
only interact with their immediate neighbours, but also reach farther to
associate with the i+2 and i+3 monomers, forming a sophisticated, funnel-like
architecture. The structure also points to a mechanism of cation selection: an
asparagine/histidine ring that constricts the narrow end of the funnel serves as
a broad cation selectivity filter, whereas an arginine/lysine ring that defines
the wide end of the funnel may selectively allow cation diffusion into the
channel. Our functional investigation using whole-cell channel recording shows
that these residues are critical for channel activity. NMR measurements of the
channel-drug complex revealed six equivalent hydrophobic pockets between the
peripheral and pore-forming helices to which amantadine or rimantadine binds,
and compound binding specifically to this position may allosterically inhibit
cation conduction by preventing the channel from opening. Our data provide a
molecular explanation for p7-mediated cation conductance and its inhibition by
adamantane derivatives.
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