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XB-ART-53760
J Med Chem 2017 Jul 13;6013:5826-5833. doi: 10.1021/acs.jmedchem.7b00546.
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α-Conotoxin [S9A]TxID Potently Discriminates between α3β4 and α6/α3β4 Nicotinic Acetylcholine Receptors.

Wu Y , Zhangsun D , Zhu X , Kaas Q , Zhangsun M , Harvey PJ , Craik DJ , McIntosh JM , Luo S .


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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.

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References [+] :
Akondi, Discovery, synthesis, and structure-activity relationships of conotoxins. 2014, Pubmed