A Noncompetitive Peptide Inhibitor of the Nicotinic Acetylcholine Receptor from Conus purpurascens Venom

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Abstract
A paralytic peptide, ψ-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 α-bungarotoxin, a competitive nAChR antagonist. Thus, ψ-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: HOOC CLYGKCRRYOGCSSASC CQR* (O = 4-trans hydroxyproline; * indicates an amidated C-terminus). The disulfide connectivity of the toxin is unrelated to the α- or the αA-conotoxins, the Conus peptide families that are competitive inhibitors of the nAChR, but shows homology to the μ-conotoxins (which are Na+ channel blockers).