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PDBsum entry 4xhe
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Acetylcholine-binding protein
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PDB id
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4xhe
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Contents |
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(+ 2 more)
216 a.a.
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204 a.a.
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References listed in PDB file
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Key reference
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Title
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Marine macrocyclic imines, Pinnatoxins a and g: structural determinants and functional properties to distinguish neuronal α7 from muscle α1(2)βγδ nachrs.
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Authors
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Y.Bourne,
G.Sulzenbacher,
Z.Radić,
R.Aráoz,
M.Reynaud,
E.Benoit,
A.Zakarian,
D.Servent,
J.Molgó,
P.Taylor,
P.Marchot.
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Ref.
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Structure, 2015,
23,
1106-1115.
[DOI no: ]
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PubMed id
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Abstract
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Pinnatoxins are macrocyclic imine phycotoxins associated with algal blooms and
shellfish toxicity. Functional analysis of pinnatoxin A and pinnatoxin G by
binding and voltage-clamp electrophysiology on membrane-embedded neuronal α7,
α4β2, α3β2, and muscle-type α12βγδ nicotinic acetylcholine receptors
(nAChRs) reveals high-affinity binding and potent antagonism for the α7 and
α12βγδ subtypes. The toxins also bind to the nAChR surrogate,
acetylcholine-binding protein (AChBP), with low Kd values reflecting slow
dissociation. Crystal structures of pinnatoxin-AChBP complexes (1.9-2.2 Å
resolution) show the multiple anchoring points of the hydrophobic portion, the
cyclic imine, and the substituted bis-spiroketal and cyclohexene ring systems of
the pinnatoxins that dictate tight binding between the opposing loops C and F at
the receptor subunit interface, as observed for the 13-desmethyl-spirolide C and
gymnodimine A congeners. Uniquely, however, the bulky bridged EF-ketal ring
specific to the pinnatoxins extends radially from the interfacial-binding pocket
to interact with the sequence-variable loop F and govern nAChR subtype
selectivity and central neurotoxicity.
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