Marine Macrocyclic Imines, Pinnatoxins A and G: Structural Determinants and Functional Properties to Distinguish Neuronal α7 from Muscle α12βγδ nAChRs

• Published in: Structure (London) 2015-06, Vol.23 (6), p.1106-1115
• Main Authors: Bourne, Yves, Sulzenbacher, Gerlind, Radić, Zoran, Aráoz, Rómulo, Reynaud, Morgane, Benoit, Evelyne, Zakarian, Armen, Servent, Denis, Molgó, Jordi, Taylor, Palmer, Marchot, Pascale
• Format: Article
• Language: English
• Subjects: Cognitive Sciences; Life Sciences; Neurobiology; Neurons and Cognition; Psychology and behavior
• ISSN: 0969-2126; 1878-4186; 1878-4186
• DOI: 10.1016/j.str.2015.04.009

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. [Display omitted] •PnTx-A and -G display high-affinity antagonism for the neuronal α7 and muscle nAChRs•Structures of the toxins bound to the soluble nAChR surrogate, AChBP, were solved•The common macrocyclic core provides multiple anchor points dictating tight binding•The unique bridged ketal ring governs nAChR subtype selectivity and CNS toxicity Pinnatoxins are macrocyclic imine phycotoxins associated with algal blooms and shellfish toxicity. Bourne et al. show that their core determinants shared with other toxins dictate high-affinity binding and potent antagonism toward the nAChRs, while their unique bulky bridged ketal ring governs selectivity for the neuronal α7 and muscle nAChRs and central neurotoxicity.