Cysteine-Rich ?-Conotoxin SII Displays Novel Interactions at the Muscle Nicotinic Acetylcholine Receptor

: alpha-Conotoxins that target muscle nicotinic acetylcholine receptors (nAChRs) commonly fall into two structural classes, frameworks I and II containing two and three disulfide bonds, respectively. Conotoxin SII is the sole member of the cysteine-rich framework II with ill-defined interactions at the nAChRs. Following directed synthesis of alpha-SII, NMR analysis revealed a well-defined structure containing a 310-helix frequently employed by framework I alpha-conotoxins; alpha-SII acted at the muscle nAChR with half-maximal inhibitory concentrations (IC50) of 120 nM (adult) and 370 nM (fetal) though weakly at neuronal nAChRs. Truncation of alpha-SII to a two disulfide bond amidated peptide with framework I disulfide connectivity led to similar activity. Surprisingly, the more constrained alpha-SII was less stable under mild reducing conditions and displayed a unique docking mode at the nAChR