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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / chemistry*
  • Carrier Proteins / metabolism
  • Cell Membrane / metabolism
  • Imines / chemistry*
  • Kinetics
  • Macrocyclic Compounds / chemistry*
  • Marine Toxins / chemistry*
  • Models, Molecular*
  • Molecular Structure
  • Patch-Clamp Techniques
  • Protein Binding
  • Protein Conformation
  • Receptors, Nicotinic / metabolism
  • Spiro Compounds / chemistry*
  • alpha7 Nicotinic Acetylcholine Receptor / antagonists & inhibitors
  • alpha7 Nicotinic Acetylcholine Receptor / metabolism


  • AChBP protein, Lymnaea
  • Alkaloids
  • Carrier Proteins
  • Imines
  • Macrocyclic Compounds
  • Marine Toxins
  • Receptors, Nicotinic
  • Spiro Compounds
  • alpha1beta1gammadelta receptor, human
  • alpha7 Nicotinic Acetylcholine Receptor
  • nicotinic receptor alpha3beta2
  • nicotinic receptor alpha4beta2
  • pinnatoxin A
  • pinnatoxin G

Associated data

  • PDB/4XHE
  • PDB/4XK9