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Structure. 2015 Jun 2;23(6):1106-15. doi: 10.1016/j.str.2015.04.009. Epub 2015 May 21.

Marine Macrocyclic Imines, Pinnatoxins A and G: Structural Determinants and Functional Properties to Distinguish Neuronal α7 from Muscle α1(2)βγδ nAChRs.

Author information

1
Aix-Marseille Université, Laboratoire Architecture et Fonction des Macromolécules Biologiques, Campus Luminy, 13288 Marseille cedex 9, France; Centre National de la Recherche Scientifique, Laboratoire Architecture et Fonction des Macromolécules Biologiques, Campus Luminy, 13288 Marseille cedex 9, France. Electronic address: yves.bourne@afmb.univ-mrs.fr.
2
Aix-Marseille Université, Laboratoire Architecture et Fonction des Macromolécules Biologiques, Campus Luminy, 13288 Marseille cedex 9, France; Centre National de la Recherche Scientifique, Laboratoire Architecture et Fonction des Macromolécules Biologiques, Campus Luminy, 13288 Marseille cedex 9, France.
3
Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093-0650, USA.
4
Institut des Neurosciences Paris-Saclay, Centre National de la Recherche Scientifique, 91190 Gif-sur-Yvette, France; Commissariat à l'Energie Atomique, iBiTecS, Service d'Ingénierie Moléculaire des Protéines, 91191 Gif-sur-Yvette, France.
5
Commissariat à l'Energie Atomique, iBiTecS, Service d'Ingénierie Moléculaire des Protéines, 91191 Gif-sur-Yvette, France.
6
Department of Chemistry and Biochemistry, University of California Santa Barbara, CA 93106-9510, USA.
7
Aix-Marseille Université, Laboratoire Architecture et Fonction des Macromolécules Biologiques, Campus Luminy, 13288 Marseille cedex 9, France; Centre National de la Recherche Scientifique, Laboratoire Architecture et Fonction des Macromolécules Biologiques, Campus Luminy, 13288 Marseille cedex 9, France. Electronic address: pascale.marchot@univ-amu.fr.

Abstract

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.

Comment in

PMID:
26004441
PMCID:
PMC4461042
DOI:
10.1016/j.str.2015.04.009
[Indexed for MEDLINE]
Free PMC Article

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