Marine Macrocyclic Imines, Pinnatoxins A and G: Structural Determinants and Functional Properties to Distinguish Neuronal alpha 7 from Muscle alpha 1(2)beta gamma delta nAChRs

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作   者：

Bourne, Yves;  Sulzenbacher, Gerlind;  Radic, Zoran;  Araoz, Romulo;  Reynaud, Morgane;  Benoit, Evelyne;  Zakarian, Armen;  Servent, Denis;  Molgo, Jordi;  Taylor, Palmer;  Marchot, Pascale; 

作者机构：

CA 93106 USA;  Lab Architecture & Fonct Macromol Biol;  CA 92093 USA;  Inst Neurosci Paris Saclay;  CEA;  F-91190 Gif Sur Yvette;  F-13288 Marseille 9;  Serv Ingn Mol Prot;  Univ Calif San Diego;  IBiTecS;  F-91191 Gif Sur Yvette;  Aix Marseille Univ;  Dept Chem & Biochem;  CNRS;  La Jolla;  Univ Calif Santa Barbara;  France;  Skaggs Sch Pharm & Pharmaceut Sci;  Dept Pharmacol;  Santa Barbara; 

期刊名称：

Structure

i s s n：

0969-2126

年卷期：

2015 年 23 卷 6 期

页   码：

1106-1115

页   码：

摘   要：

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 alpha 7, alpha 4 beta 2, alpha 3 beta 2, and muscle-type alpha 1(2)beta gamma delta nicotinic acetylcholine receptors (nAChRs) reveals high-affinity binding and potent antagonism for the alpha 7 and alpha 1(2)beta gamma delta subtypes. The toxins also bind to the nAChR surrogate, acetylcholine-binding protein (AChBP), with low K-d values reflecting slow dissociation. Crystal structures of pinnatoxin-AChBP complexes (1.9-2.2 angstrom 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.