4XHE

Marine Macrocyclic Imines, Pinnatoxins A and G: Structural Determinants and Functional Properties to Distinguish Neuronal alpha 7 from Muscle alpha 12 beta gamma delta nAChRs.

(2015) Structure 23: 1106-1115

• PubMed: 26004441 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1016/j.str.2015.04.009
• Primary Citation of Related Structures:  
  4XHE, 4XK9


• PubMed 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.

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Organizational Affiliation: 

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.