Abstract
A high resolution structure of alpha-conotoxin EI has been determined by (1)H NMR spectroscopy and molecular modeling. alpha-Conotoxin EI has the same disulfide framework as alpha 4/7 conotoxins targeting neuronal nicotinic acetylcholine receptors but antagonizes the neuromuscular receptor as do the alpha 3/5 and alpha A conotoxins. The unique binding preference of alpha-conotoxin EI to the alpha(1)/delta subunit interface of Torpedo neuromuscular receptor makes it a valuable structural template for superposition of various alpha-conotoxins possessing distinct receptor subtype specificities. Structural comparison of alpha-conotoxin EI with the gamma-subunit favoring alpha-conotoxin GI suggests that the Torpedo delta-subunit preference of the former originates from its second loop. Superposition of three-dimensional structures of seven alpha-conotoxins reveals that the estimated size of the toxin-binding pocket in nicotinic acetylcholine receptor is approximately 20 A (height) x 20 A (width) x 15 A (thickness).
Highlights
A high resolution structure of ␣-conotoxin EI has been determined by 1H NMR spectroscopy and molecular modeling. ␣-Conotoxin EI has the same disulfide framework as ␣4/7 conotoxins targeting neuronal nicotinic acetylcholine receptors but antagonizes the neuromuscular receptor as do the ␣3/5 and ␣A conotoxins
Proper understanding of ligand-nicotinic acetylcholine receptors (nAChRs) interactions would require precise knowledge of which amino acid residues or pharmacophores are involved in ligand-receptor binding as well as how such residues are arranged in the three-dimensional space
Knowledge of relative spatial orientations of important receptor-binding pharmacophores in various ligands can be obtained from high resolution three-dimensional structures of several nAChR ligands (13, 18 –33) and has been useful in studying ligand-nAChR interactions even in the absence of an atomic resolution structure of nAChR
Summary
RDOCCYHPTCNMSNPQIC* GCCSNPVCHLEHSNLC* GCCSLPPCAANNPDYC* GCCSLPPCALSNPDYC* GCCSYPPCFATNSDYC* GCCSYPPCFATNPD C* GCCSYPPCFATNSGYC* GCCSDPRCNMNNPDYC*. A The first capital letter indicates the species origin. B The asterisk indicates an amidated C terminus. C For the ␣3/5 subfamily and ␣-conotoxin EI, the specificity is for Torpedo receptor. D References include reports of three-dimensional structures when available. Molecular features within ␣-conotoxins that confer receptor subtype specificity
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