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PDBsum entry 1tch
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DOI no:
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Biochemistry
31:12577-12584
(1992)
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PubMed id:
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Structure-activity relationships of mu-conotoxin GIIIA: structure determination of active and inactive sodium channel blocker peptides by NMR and simulated annealing calculations.
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K.Wakamatsu,
D.Kohda,
H.Hatanaka,
J.M.Lancelin,
Y.Ishida,
M.Oya,
H.Nakamura,
F.Inagaki,
K.Sato.
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ABSTRACT
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A synthetic replacement study of the amino acid residues of mu-conotoxin GIIIA,
a peptide blocker for muscle sodium channels, has recently shown that the
conformation formed by three disulfide bridges and the molecular basicity,
especially the one around the Arg13 residue, are important for blocking
activity. In the present study, we determined the three-dimensional structure of
an inactive analog, [Ala13]mu-conotoxin GIIIA, and refined that of the native
toxin by NMR spectroscopy combined with simulated annealing calculations. The
atomic root-mean-square difference of the mutant from the native conotoxin was
0.62 A for the backbone atoms (N, C alpha, C') of all residues except for the
two terminal residues. The observation that the replacement of Arg13 by Ala13
does not significantly change the molecular conformation suggests that the loss
of activity is not due to the conformational change but to the direct
interaction of the essential Arg13 residue with the sodium channel molecules. In
the determined structure, important residues for the activity, Arg13, Lys16,
Hyp(hydroxyproline)17, and Arg19, are clustered on one side of the molecule, an
observation which suggests that this face of the molecule associates with the
receptor site of sodium channels. The hydroxyl group of Hyp17 is suggested to
interact with the channel site with which the essential hydroxyl groups of
tetrodotoxin and saxitoxin interact.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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T.S.Han,
M.M.Zhang,
A.Walewska,
P.Gruszczynski,
C.R.Robertson,
T.E.Cheatham,
D.Yoshikami,
B.M.Olivera,
and
G.Bulaj
(2009).
Structurally minimized mu-conotoxin analogues as sodium channel blockers: implications for designing conopeptide-based therapeutics.
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ChemMedChem,
4,
406-414.
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C.I.Schroeder,
J.Ekberg,
K.J.Nielsen,
D.Adams,
M.L.Loughnan,
L.Thomas,
D.J.Adams,
P.F.Alewood,
and
R.J.Lewis
(2008).
Neuronally micro-conotoxins from Conus striatus utilize an alpha-helical motif to target mammalian sodium channels.
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J Biol Chem,
283,
21621-21628.
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I.Hudáky,
and
A.Perczel
(2008).
Prolylproline unit in model peptides and in fragments from databases.
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Proteins,
70,
1389-1407.
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U.C.Marx,
N.L.Daly,
and
D.J.Craik
(2006).
NMR of conotoxins: structural features and an analysis of chemical shifts of post-translationally modified amino acids.
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Magn Reson Chem,
44,
S41-S50.
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D.B.Tikhonov,
and
B.S.Zhorov
(2005).
Modeling P-loops domain of sodium channel: homology with potassium channels and interaction with ligands.
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Biophys J,
88,
184-197.
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L.Verdier,
A.Al-Sabi,
J.E.Rivier,
B.M.Olivera,
H.Terlau,
and
T.Carlomagno
(2005).
Identification of a novel pharmacophore for peptide toxins interacting with K+ channels.
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J Biol Chem,
280,
21246-21255.
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D.Li,
Y.Xiao,
X.Xu,
X.Xiong,
S.Lu,
Z.Liu,
Q.Zhu,
M.Wang,
X.Gu,
and
S.Liang
(2004).
Structure--activity relationships of hainantoxin-IV and structure determination of active and inactive sodium channel blockers.
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J Biol Chem,
279,
37734-37740.
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PDB codes:
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I.Ibañez-Tallon,
H.Wen,
J.M.Miwa,
J.Xing,
A.B.Tekinay,
F.Ono,
P.Brehm,
and
N.Heintz
(2004).
Tethering naturally occurring peptide toxins for cell-autonomous modulation of ion channels and receptors in vivo.
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Neuron,
43,
305-311.
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R.A.Li,
and
G.F.Tomaselli
(2004).
Using the deadly mu-conotoxins as probes of voltage-gated sodium channels.
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Toxicon,
44,
117-122.
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D.W.Keizer,
P.J.West,
E.F.Lee,
D.Yoshikami,
B.M.Olivera,
G.Bulaj,
and
R.S.Norton
(2003).
Structural basis for tetrodotoxin-resistant sodium channel binding by mu-conotoxin SmIIIA.
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J Biol Chem,
278,
46805-46813.
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PDB code:
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K.Hui,
D.McIntyre,
and
R.J.French
(2003).
Conotoxins as sensors of local pH and electrostatic potential in the outer vestibule of the sodium channel.
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J Gen Physiol,
122,
63-79.
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R.A.Li,
I.L.Ennis,
T.Xue,
H.M.Nguyen,
G.F.Tomaselli,
A.L.Goldin,
and
E.Marbán
(2003).
Molecular basis of isoform-specific micro-conotoxin block of cardiac, skeletal muscle, and brain Na+ channels.
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J Biol Chem,
278,
8717-8724.
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R.A.Li,
K.Hui,
R.J.French,
K.Sato,
C.A.Henrikson,
G.F.Tomaselli,
and
E.Marbán
(2003).
Dependence of mu-conotoxin block of sodium channels on ionic strength but not on the permeating [Na+]: implications for the distinctive mechanistic interactions between Na+ and K+ channel pore-blocking toxins and their molecular targets.
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J Biol Chem,
278,
30912-30919.
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T.Xue,
I.L.Ennis,
K.Sato,
R.J.French,
and
R.A.Li
(2003).
Novel interactions identified between micro -Conotoxin and the Na+ channel domain I P-loop: implications for toxin-pore binding geometry.
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Biophys J,
85,
2299-2310.
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K.Hui,
G.Lipkind,
H.A.Fozzard,
and
R.J.French
(2002).
Electrostatic and steric contributions to block of the skeletal muscle sodium channel by mu-conotoxin.
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J Gen Physiol,
119,
45-54.
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L.A.Miles,
C.Y.Dy,
J.Nielsen,
K.J.Barnham,
M.G.Hinds,
B.M.Olivera,
G.Bulaj,
and
R.S.Norton
(2002).
Structure of a novel P-superfamily spasmodic conotoxin reveals an inhibitory cystine knot motif.
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J Biol Chem,
277,
43033-43040.
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PDB code:
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R.A.Li,
I.L.Ennis,
G.F.Tomaselli,
R.J.French,
and
E.Marbán
(2001).
Latent specificity of molecular recognition in sodium channels engineered to discriminate between two "indistinguishable" mu-conotoxins.
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Biochemistry,
40,
6002-6008.
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A.Mosbah,
R.Kharrat,
Z.Fajloun,
J.G.Renisio,
E.Blanc,
J.M.Sabatier,
M.El Ayeb,
and
H.Darbon
(2000).
A new fold in the scorpion toxin family, associated with an activity on a ryanodine-sensitive calcium channel.
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Proteins,
40,
436-442.
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PDB code:
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C.Bernard,
C.Legros,
G.Ferrat,
U.Bischoff,
A.Marquardt,
O.Pongs,
and
H.Darbon
(2000).
Solution structure of hpTX2, a toxin from Heteropoda venatoria spider that blocks Kv4.2 potassium channel.
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Protein Sci,
9,
2059-2067.
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PDB code:
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S.C.Dudley,
N.Chang,
J.Hall,
G.Lipkind,
H.A.Fozzard,
and
R.J.French
(2000).
mu-conotoxin GIIIA interactions with the voltage-gated Na(+) channel predict a clockwise arrangement of the domains.
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J Gen Physiol,
116,
679-690.
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J.M.McIntosh,
A.D.Santos,
and
B.M.Olivera
(1999).
Conus peptides targeted to specific nicotinic acetylcholine receptor subtypes.
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Annu Rev Biochem,
68,
59-88.
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S.S.Mitchell,
K.J.Shon,
M.P.Foster,
D.R.Davis,
B.M.Olivera,
and
C.M.Ireland
(1998).
Three-dimensional solution structure of conotoxin psi-PIIIE, an acetylcholine gated ion channel antagonist.
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Biochemistry,
37,
1215-1220.
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PDB code:
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A.C.Rigby,
J.D.Baleja,
B.C.Furie,
and
B.Furie
(1997).
Three-dimensional structure of a gamma-carboxyglutamic acid-containing conotoxin, conantokin G, from the marine snail Conus geographus: the metal-free conformer.
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Biochemistry,
36,
6906-6914.
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PDB code:
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J.M.Hill,
P.F.Alewood,
and
D.J.Craik
(1997).
Solution structure of the sodium channel antagonist conotoxin GS: a new molecular caliper for probing sodium channel geometry.
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Structure,
5,
571-583.
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PDB code:
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R.A.Li,
R.G.Tsushima,
R.G.Kallen,
and
P.H.Backx
(1997).
Pore residues critical for mu-CTX binding to rat skeletal muscle Na+ channels revealed by cysteine mutagenesis.
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Biophys J,
73,
1874-1884.
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J.M.Hill,
P.F.Alewood,
and
D.J.Craik
(1996).
Three-dimensional solution structure of mu-conotoxin GIIIB, a specific blocker of skeletal muscle sodium channels.
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Biochemistry,
35,
8824-8835.
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PDB code:
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J.M.Lancelin,
M.F.Foray,
M.Poncin,
M.Hollecker,
and
D.Marion
(1994).
Proteinase inhibitor homologues as potassium channel blockers.
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Nat Struct Biol,
1,
246-250.
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PDB codes:
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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