alpha-Conotoxin MII, isolated from Conus magus, is a potent peptidic toxin which specifically targets the mammalian neuronal nicotinic acetylcholine receptor, alpha3beta2 subtype. The three-dimensional structure of alpha-conotoxin MII in aqueous solution has been determined by two-dimensional 1H NMR spectroscopy. NOE-derived distances, refined by an iterative relaxation matrix approach, as well as dihedral and chirality restraints were used in high-temperature biphasic simulated annealing calculations. Fourteen minimum energy structures out of 50 subjected to the SA simulations were chosen for evaluation; these 14 structures have a final RMS deviation of 0.76 +/- 0.31 and 1.35 +/- 0.34 A for the backbone and heavy atoms, respectively. The overall structure is unusually well-defined due to a large helical component around the two disulfide bridges. The principal backbone folding motif may be common to a subclass of alpha-conotoxins. There are two distinct surfaces on the molecule almost at right angles to one another. One entirely consists of the hydrophobic residues Gly1, Cys2, Cys3, Leu15, and Cys16. The second comprises the hydrophilic residues Glu11, His12, Ser13, and Asn14. These surfaces on the ligand could be essential for the subtype-specific recognition of the receptor.

A paralytic peptide, psi-conotoxin Piiie has been purified and characterized from Conus purpurascens venom. Electrophysiological studies indicate that the peptide inhibits the nicotinic acetylcholine receptor (nAChR). However, the peptide does not block the binding of alpha-bungarotoxin, a competitive nAChR antagonist. Thus, psi-conotoxin Piiie appears to inhibit the receptor at a site other than the acetylcholine-binding site. As ascertained by sequence analysis, mass spectrometry, and chemical synthesis, the peptide has the following covalent structure: HOOCCLYGKCRRYOGCSSASCCQR* (O = 4-trans hydroxyproline; * indicates an amidated C-terminus). The disulfide connectivity of the toxin is unrelated to the alpha- or the alphaA-conotoxins, the Conus peptide families that are competitive inhibitors of the nAChR, but shows homology to the mu-conotoxins (which are Na+ channel blockers).