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

Journal Article


Abstract


  • α-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 α-SII, NMR analysis revealed a well-defined structure containing a 310-helix frequently employed by framework I α-conotoxins; α-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 α-SII to a two disulfide bond amidated peptide with framework I disulfide connectivity led to similar activity. Surprisingly, the more constrained α-SII was less stable under mild reducing conditions and displayed a unique docking mode at the nAChR.

Publication Date


  • 2022

Citation


  • Wilhelm, P., Luna-Ramirez, K., Chin, Y. K. Y., Dekan, Z., Abraham, N., Tae, H. S., . . . Alewood, P. F. (2022). Cysteine-Rich a-Conotoxin SII Displays Novel Interactions at the Muscle Nicotinic Acetylcholine Receptor. ACS Chemical Neuroscience, 13(8), 1245-1250. doi:10.1021/acschemneuro.1c00857

Scopus Eid


  • 2-s2.0-85127885540

Start Page


  • 1245

End Page


  • 1250

Volume


  • 13

Issue


  • 8

Abstract


  • α-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 α-SII, NMR analysis revealed a well-defined structure containing a 310-helix frequently employed by framework I α-conotoxins; α-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 α-SII to a two disulfide bond amidated peptide with framework I disulfide connectivity led to similar activity. Surprisingly, the more constrained α-SII was less stable under mild reducing conditions and displayed a unique docking mode at the nAChR.

Publication Date


  • 2022

Citation


  • Wilhelm, P., Luna-Ramirez, K., Chin, Y. K. Y., Dekan, Z., Abraham, N., Tae, H. S., . . . Alewood, P. F. (2022). Cysteine-Rich a-Conotoxin SII Displays Novel Interactions at the Muscle Nicotinic Acetylcholine Receptor. ACS Chemical Neuroscience, 13(8), 1245-1250. doi:10.1021/acschemneuro.1c00857

Scopus Eid


  • 2-s2.0-85127885540

Start Page


  • 1245

End Page


  • 1250

Volume


  • 13

Issue


  • 8