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PDBsum entry 2m4x
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References listed in PDB file
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Key reference
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Title
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Analysis of the structural and molecular basis of voltage-Sensitive sodium channel inhibition by the spider toxin huwentoxin-Iv (μ-Trtx-Hh2a).
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Authors
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N.A.Minassian,
A.Gibbs,
A.Y.Shih,
Y.Liu,
R.A.Neff,
S.W.Sutton,
T.Mirzadegan,
J.Connor,
R.Fellows,
M.Husovsky,
S.Nelson,
M.J.Hunter,
M.Flinspach,
A.D.Wickenden.
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Ref.
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J Biol Chem, 2013,
288,
22707-22720.
[DOI no: ]
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PubMed id
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Abstract
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Voltage-gated sodium channels (VGSCs) are essential to the normal function of
the vertebrate nervous system. Aberrant function of VGSCs underlies a variety of
disorders, including epilepsy, arrhythmia, and pain. A large number of animal
toxins target these ion channels and may have significant therapeutic potential.
Most of these toxins, however, have not been characterized in detail. Here, by
combining patch clamp electrophysiology and radioligand binding studies with
peptide mutagenesis, NMR structure determination, and molecular modeling, we
have revealed key molecular determinants of the interaction between the
tarantula toxin huwentoxin-IV and two VGSC isoforms, Nav1.7 and Nav1.2. Nine
huwentoxin-IV residues (F6A, P11A, D14A, L22A, S25A, W30A, K32A, Y33A, and I35A)
were important for block of Nav1.7 and Nav1.2. Importantly, molecular dynamics
simulations and NMR studies indicated that folding was normal for several key
mutants, suggesting that these amino acids probably make specific interactions
with sodium channel residues. Additionally, we identified several amino acids
(F6A, K18A, R26A, and K27A) that are involved in isoform-specific VGSC
interactions. Our structural and functional data were used to model the docking
of huwentoxin-IV into the domain II voltage sensor of Nav1.7. The model predicts
that a hydrophobic patch composed of Trp-30 and Phe-6, along with the basic
Lys-32 residue, docks into a groove formed by the Nav1.7 S1-S2 and S3-S4 loops.
These results provide new insight into the structural and molecular basis of
sodium channel block by huwentoxin-IV and may provide a basis for the rational
design of toxin-based peptides with improved VGSC potency and/or selectivity.
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