Crystal structure of an acetylcholinesterase–fasciculin complex: interaction of a three-fingered toxin from snake venom with its target

Abstract

Two conserved aromatic residues in the AChE peripheral anionic site make important contacts with FAS. The absence of these residues from chicken and insect AChEs and from butyrylcholinesterase explains the very large reduction in the affinity of these enzymes for FAS. Several basic residues in FAS make important contacts with AChE. The complementarity between FAS and AChE is unusual, inasmuch as it involves a number of charged residues, but lacks any intermolecular salt linkages.

Pairwise Electrostatic Interactions between α-Neurotoxins and γ, δ, and ε Subunits of the Nicotinic Acetylcholine Receptor

“…The ␣-neurotoxins share a common basic structure consisting of three large polypeptide loops emerging from a smaller globular core (10). X-ray crystallographic studies of a structurally homologous toxin, fasciculin, bound to its target acetylcholinesterase, reveal a high degree of complementarity between the surfaces and an interfacial contact zone extending over 1200 Å and encompassing nearly 30% of the ␣-toxin surface (11,12).…”

“…Of the ϳ1200 Å 2 of interfacial contact expected for an ␣-toxin receptor interaction with a K D Յ 100 pM (11,12,38,41,42), the ␥ subunit may only contribute 40 -60% of the total interfacial contact area. An analysis of this set of charged ␣ toxin residues with point charges on the ␣ subunit constitutes a next step in the ligand docking refinement.…”

“…The ␣-neurotoxins share a common basic structure consisting of three large polypeptide loops emerging from a smaller globular core (10). X-ray crystallographic studies of a structurally homologous toxin, fasciculin, bound to its target acetylcholinesterase, reveal a high degree of complementarity between the surfaces and an interfacial contact zone extending over 1200 Å and encompassing nearly 30% of the ␣-toxin surface (11,12).In previous investigations of ␣-neurotoxin-nAChR interactions, we found that the binding site formed at the ␣⑀ interface shows unique resistance to binding Naja mossambica mossambica I (NmmI) toxin due to the presence of Thr 176 and Ala 177 in the ⑀ subunit. Furthermore, substitution of ⑀ subunit residues at homologous positions in the ␥ subunit demonstrated a strong linkage between Lys 27 on the second loop of NmmI ␣-toxin and Glu 176 on the ␥ subunit of the receptor (13).…”

Crystal Structure of Mouse Acetylcholinesterase

“…However, it was not possible to distinguish species-related differences from changes in conformation accompanying Fas2 binding. Indeed, little difference in TcAChE conformation was observed between structures of the apoenzyme (14) and the Fas2 complex (16). In addition, currently available crystal structures of AChE reveal the entrance of the active site gorge to be either occluded by a symmetryrelated molecule (14,17,18) or sealed with high surface complementarity by Fas2 (15,16), therefore precluding structural analysis of an unprotected peripheral anionic site region.…”

Recognition of spatial motifs in protein structures 1 1Edited by J. Thornton

“…Harel et al (1995), in their analysis of the interface of Torpedo californica acetylcholinesterase and the snake toxin fasciculin, encountered a seemingly unusual stacking interaction between a tryptophan ring and the S d -C e moiety of a methionine residue. Closer scrutiny with SPASM, however, revealed the existence of several similar, albeit not identical, interactions that occur in a variety of proteins, including the anionic site of acetylcholinesterase itself.…”