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PDBsum entry 3bkd
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Viral protein, membrane protein
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PDB id
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3bkd
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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 the function and inhibition of an influenza virus proton channel.
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Authors
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A.L.Stouffer,
R.Acharya,
D.Salom,
A.S.Levine,
L.Di costanzo,
C.S.Soto,
V.Tereshko,
V.Nanda,
S.Stayrook,
W.F.Degrado.
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Ref.
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Nature, 2008,
451,
596-599.
[DOI no: ]
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PubMed id
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Abstract
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The M2 protein from influenza A virus is a pH-activated proton channel that
mediates acidification of the interior of viral particles entrapped in
endosomes. M2 is the target of the anti-influenza drugs amantadine and
rimantadine; recently, resistance to these drugs in humans, birds and pigs has
reached more than 90% (ref. 1). Here we describe the crystal structure of the
transmembrane-spanning region of the homotetrameric protein in the presence and
absence of the channel-blocking drug amantadine. pH-dependent structural changes
occur near a set of conserved His and Trp residues that are involved in proton
gating. The drug-binding site is lined by residues that are mutated in
amantadine-resistant viruses. Binding of amantadine physically occludes the
pore, and might also perturb the pK(a) of the critical His residue. The
structure provides a starting point for solving the problem of resistance to
M2-channel blockers.
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Figure 2.
Figure 2: Asymmetric structure of the C-terminal His/Trp gate of
M2TM. a, Crystal structure of the tetramer viewed from the
inside of the virus, with the helices labelled A–D. b, In the
C–D interface, Asp 44 and Arg 45 form a salt bridge, and His
37 and Trp 41 engage in an inter-subunit edge-on aromatic
interaction. c, These residues do not interact at the A–B
interface.
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Figure 4.
Figure 4: Minimal mechanism of activation and conductance
through the channel. Two helices of the tetramer and one
protonation event are shown for simplicity.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(2008,
451,
596-599)
copyright 2008.
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