PDBsum entry 4xhe

Acetylcholine-binding protein

PDB id: 4xhe

Contents

Protein chains

(+ 2 more) 216 a.a.

204 a.a.

Ligands

40P ×10

Metals

_CA ×3

_CL ×2

Waters ×1841

PDB id:

4xhe

Name:

Acetylcholine-binding protein

Title:

Crystal structure of a-achbp in complex with pinnatoxin a

Structure:

Soluble acetylcholine receptor. Chain: a, b, c, d, e, f, g, h, i, j. Fragment: unp residues 18-225. Engineered: yes

Source:

Aplysia californica. California sea hare. Organism_taxid: 6500. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek293s gnt1-

Resolution:

1.90Å R-factor: 0.175 R-free: 0.216

Authors:

Y.Bourne,G.Sulzenbacher,P.Marchot

Key ref:

Y.Bourne et al. (2015). Marine Macrocyclic Imines, Pinnatoxins A and G: Structural Determinants and Functional Properties to Distinguish Neuronal α7 from Muscle α1(2)βγδ nAChRs. Structure, 23, 1106-1115. PubMed id: 26004441 DOI: 10.1016/j.str.2015.04.009

Date:

05-Jan-15 Release date: 03-Jun-15

Protein chains

Q8WSF8  (Q8WSF8_APLCA) -  Soluble acetylcholine receptor from Aplysia californica

Seq: 236 a.a.

Struc: 216 a.a.*

Protein chains

Q8WSF8  (Q8WSF8_APLCA) -  Soluble acetylcholine receptor from Aplysia californica

Seq: 236 a.a.

Struc: 204 a.a.*

* PDB and UniProt seqs differ at 9 residue positions (black crosses)

DOI no: 10.1016/j.str.2015.04.009

Structure 23:1106-1115 (2015)

PubMed id: 26004441

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

Y.Bourne, G.Sulzenbacher, Z.Radić, R.Aráoz, M.Reynaud, E.Benoit, A.Zakarian, D.Servent, J.Molgó, P.Taylor, P.Marchot.

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.