Journal of Medicinal Chemistry
Journal of Medicinal Chemistry
5 years ago

α-Conotoxin [S9A]TxID Potently Discriminates between α3β4 and α6/α3β4 Nicotinic Acetylcholine Receptors

α-Conotoxin [S9A]TxID Potently Discriminates between α3β4 and α6/α3β4 Nicotinic Acetylcholine Receptors
Manqi Zhangsun, J. Michael McIntosh, David J. Craik, Peta J. Harvey, Xiaopeng Zhu, Sulan Luo, Quentin Kaas, Dongting Zhangsun, Yong Wu
α3β4 nAChRs have been implicated in various pathophysiological conditions. However, the expression profile of α3β4 nAChRs and α6/α3β4 nAChRs overlap in a variety of tissues. To distinguish between these two subtypes, we redesigned peptide 1 (α-conotoxin TxID), which inhibits α3β4 and α6/α3β4 nAChR subtypes. We systematically mutated 1 to evaluate analogue selectivity for α3β4 vs α6/α3β4 nAChRs expressed in Xenopus laevis oocytes. One analogue, peptide 7 ([S9A]TxID), had 46-fold greater potency for α3β4 versus α6/α3β4 nAChRs. Peptide 7 had IC50s > 10 μM for other nAChR subtypes. Molecular dynamics simulations suggested that Ser-9 of TxID was involved in a weak hydrogen bond with β4 Lys-81 in the α6β4 binding site but not in the α3β4 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 α3β4 nAChRs.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00546

DOI: 10.1021/acs.jmedchem.7b00546

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