4XHE

Crystal Structure of A-AChBP in complex with pinnatoxin A

Summary for 4XHE

• Entry DOI: 10.2210/pdb4xhe/pdb
• Descriptor: Soluble acetylcholine receptor, Pinnatoxin A, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: receptor, phycotoxin, pinnatoxin, membrane protein, acetylcholine-binding protein
• Biological source: Aplysia californica (California sea hare)
• Total number of polymer chains: 10
• Total formula weight: 254585.22

Authors

Bourne, Y.,Sulzenbacher, G.,Marchot, P. (deposition date: 2015-01-05, release date: 2015-06-03, Last modification date: 2024-11-13)

Primary citation

Bourne, Y.,Sulzenbacher, G.,Radic, Z.,Araoz, R.,Reynaud, M.,Benoit, E.,Zakarian, A.,Servent, D.,Molgo, J.,Taylor, P.,Marchot, P.
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.
Structure, 23:1106-1115, 2015

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.

PubMed: 26004441
DOI: 10.1016/j.str.2015.04.009

Experimental method

X-RAY DIFFRACTION (1.9 Å)