Single-Disulfide Conopeptide Czon1107, an Allosteric Antagonist of the Human α3β4 Nicotinic Acetylcholine Receptor

Conopeptides are peptides in the venom of marine cone snails that are used for capturing prey or as a defense against predators. A new cysteine-poor conopeptide, Czon1107, has exhibited non-competitive inhibition with an undefined allosteric mechanism in the human (h) α3β4 nicotinic acetylcholine receptors (nAChRs). In this study, the binding mode of Czon1107 to hα3β4 nAChR was investigated using molecular dynamics simulations coupled with mutagenesis studies of the peptide and electrophysiology studies on heterologous hα3β4 nAChRs. Overall, this study clarifies the structure–activity relationship of Czon1107 and hα3β4 nAChR and provides an important experimental and theoretical basis for the development of new peptide drugs.