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PDBsum entry 2n8h
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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 inhibition of voltage-Gated sodium channels by conotoxin μo§-Gviij.
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Authors
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B.R.Green,
J.Gajewiak,
S.Chhabra,
J.J.Skalicky,
M.M.Zhang,
J.E.Rivier,
G.Bulaj,
B.M.Olivera,
D.Yoshikami,
R.S.Norton.
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Ref.
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J Biol Chem, 2016,
291,
7205-7220.
[DOI no: ]
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PubMed id
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Abstract
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Cone snail toxins are well known blockers of voltage-gated sodium channels, a
property that is of broad interest in biology and therapeutically in treating
neuropathic pain and neurological disorders. Although most conotoxin channel
blockers function by direct binding to a channel and disrupting its normal ion
movement, conotoxin μO§-GVIIJ channel blocking is unique, using both favorable
binding interactions with the channel and a direct tether via an intermolecular
disulfide bond. Disulfide exchange is possible because conotoxin μO§-GVIIJ
contains anS-cysteinylated Cys-24 residue that is capable of exchanging with a
free cysteine thiol on the channel surface. Here, we present the solution
structure of an analog of μO§-GVIIJ (GVIIJ[C24S]) and the results of
structure-activity studies with synthetic μO§-GVIIJ variants. GVIIJ[C24S]
adopts an inhibitor cystine knot structure, with two antiparallel β-strands
stabilized by three disulfide bridges. The loop region linking the β-strands
(loop 4) presents residue 24 in a configuration where it could bind to the
proposed free cysteine of the channel (Cys-910, rat NaV1.2 numbering; at site
8). The structure-activity study shows that three residues (Lys-12, Arg-14, and
Tyr-16) located in loop 2 and spatially close to residue 24 were also important
for functional activity. We propose that the interaction of μO§-GVIIJ with the
channel depends on not only disulfide tethering via Cys-24 to a free cysteine at
site 8 on the channel but also the participation of key residues of μO§-GVIIJ
on a distinct surface of the peptide.
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