Determination
of the α‑Conotoxin Vc1.1
Binding Site on the α9α10 Nicotinic Acetylcholine Receptor
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Abstract
α-Conotoxin Vc1.1 specifically
and potently inhibits the
nicotinic acetylcholine receptor subtype α9α10 (α9α10
nAChR) and is a potential novel treatment for neuropathic pain. Here,
we used a combination of computational modeling and electrophysiology
experiments to determine the Vc1.1 binding site on the α9α10
nAChR. Interactions of Vc1.1 with two probable binding sites, α9α10
and α10α9, were modeled. Mutational energies calculated
by assuming specific interactions in the α10α9 binding
site correlated better with electrophysiological recordings than those
assuming interactions with the α9α10 binding site. Two
novel Vc1.1 analogues, [N9F]Vc1.1 and [N9W]Vc1.1, were predicted to
have large differences in affinity between the two binding sites.
Data from functional studies were consistent with computational predictions
that assumed preferred binding of Vc1.1 to the α10α9 pocket.
Moreover, our modeling study suggested that a single hydrogen bond
formed between Vc1.1 and position 59 of the α10α9 pocket
confers specificity to rat versus human α9α10 nAChRs