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Crystal Structure of A-AChBP in complex with pinnatoxin A
Structural highlights
FunctionPublication Abstract from PubMedPinnatoxins 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 alpha7, alpha4beta2, alpha3beta2, and muscle-type alpha12betagammadelta nicotinic acetylcholine receptors (nAChRs) reveals high-affinity binding and potent antagonism for the alpha7 and alpha12betagammadelta 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 A 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. Marine Macrocyclic Imines, Pinnatoxins A and G: Structural Determinants and Functional Properties to Distinguish Neuronal alpha7 from Muscle alpha1betagammadelta nAChRs.,Bourne Y, Sulzenbacher G, Radic Z, Araoz R, Reynaud M, Benoit E, Zakarian A, Servent D, Molgo J, Taylor P, Marchot P Structure. 2015 May 15. pii: S0969-2126(15)00138-0. doi:, 10.1016/j.str.2015.04.009. PMID:26004441[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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