Solution conformation of alpha-conotoxin EI, a neuromuscular toxin specific for the α₁/δ subunit interface of Torpedo nicotinic acetylcholine receptor

Abstract

A high resolution structure of α-conotoxin EI has been determined by 1H NMR spectroscopy and molecular modeling. α-Conotoxin EI has the same disulfide framework as α4/7 conotoxins targeting neuronal nicotinic acetylcholine receptors but antagonizes the neuromuscular receptor as do the α3/5 and αA conotoxins. The unique binding preference of α-conotoxin EI to the α1/δ subunit interface of Torpedo neuromuscular receptor makes it a valuable structural template for superposition of various α-conotoxins possessing distinct receptor subtype specificities. Structural comparison of α-conotoxin EI with the γ-subunit favoring α-conotoxin GI suggests that the Torpedo α-subunit preference of the former originates from its second loop. Superposition of three-dimensional structures of seven α-conotoxins reveals that the estimated size of the toxin-binding pocket in nicotinic acetylcholine receptor is ∼20 ? (height) × 20 ? (width) × 15 ? (thickness).