?-Conotoxin [S9A]TxID Potently Discriminates between ?3?4 and ?6/?3?4 Nicotinic Acetylcholine Receptors.

ABSTRACT: ?3?4 nAChRs have been implicated in various pathophysiological conditions. However, the expression profile of ?3?4 nAChRs and ?6/?3?4 nAChRs overlap in a variety of tissues. To distinguish between these two subtypes, we redesigned peptide 1 (?-conotoxin TxID), which inhibits ?3?4 and ?6/?3?4 nAChR subtypes. We systematically mutated 1 to evaluate analogue selectivity for ?3?4 vs ?6/?3?4 nAChRs expressed in Xenopus laevis oocytes. One analogue, peptide 7 ([S9A]TxID), had 46-fold greater potency for ?3?4 versus ?6/?3?4 nAChRs. Peptide 7 had IC50s > 10 ?M for other nAChR subtypes. Molecular dynamics simulations suggested that Ser-9 of TxID was involved in a weak hydrogen bond with ?4 Lys-81 in the ?6?4 binding site but not in the ?3?4 binding site. When Ser-9 was substituted by an Ala, this hydrogen bond interaction was disrupted. These results provide further molecular insights into the selectivity of 7 and provide a guide for designing ligands that block ?3?4 nAChRs.

SUBMITTER: Wu Y 

PROVIDER: S-EPMC5572761 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature