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PDBsum entry 2fqc
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References listed in PDB file
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Key reference
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Title
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A novel conotoxin inhibitor of kv1.6 channel and nachr subtypes defines a new superfamily of conotoxins.
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Authors
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J.S.Imperial,
P.S.Bansal,
P.F.Alewood,
N.L.Daly,
D.J.Craik,
A.Sporning,
H.Terlau,
E.López-Vera,
P.K.Bandyopadhyay,
B.M.Olivera.
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Ref.
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Biochemistry, 2006,
45,
8331-8340.
[DOI no: ]
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PubMed id
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Abstract
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Using assay-directed fractionation of the venom from the vermivorous cone snail
Conus planorbis, we isolated a new conotoxin, designated pl14a, with potent
activity at both nicotinic acetylcholine receptors and a voltage-gated potassium
channel subtype. pl14a contains 25 amino acid residues with an amidated
C-terminus, an elongated N-terminal tail (six residues), and two disulfide bonds
(1-3, 2-4 connectivity) in a novel framework distinct from other conotoxins. The
peptide was chemically synthesized, and its three-dimensional structure was
demonstrated to be well-defined, with an alpha-helix and two 3(10)-helices
present. Analysis of a cDNA clone encoding the prepropeptide precursor of pl14a
revealed a novel signal sequence, indicating that pl14a belongs to a new gene
superfamily, the J-conotoxin superfamily. Five additional peptides in the
J-superfamily were identified. Intracranial injection of pl14a in mice elicited
excitatory symptoms that included shaking, rapid circling, barrel rolling, and
seizures. Using the oocyte heterologous expression system, pl14a was shown to
inhibit both a K+ channel subtype (Kv1.6, IC50 = 1.59 microM) and neuronal (IC50
= 8.7 microM for alpha3beta4) and neuromuscular (IC50 = 0.54 microM for
alpha1beta1 epsilondelta) subtypes of the nicotinic acetylcholine receptor
(nAChR). Similarities in sequence and structure are apparent between the middle
loop of pl14a and the second loop of a number of alpha-conotoxins. This is the
first conotoxin shown to affect the activity of both voltage-gated and
ligand-gated ion channels.
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