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

Wu, Yong, Zhangsun, Dongting, Zhu, Xiaopeng, Kaas, Quentin, Zhangsun, Manqi, Harvey, Peta J., Craik, David J., McIntosh, J. Michael and Luo, Sulan (2017) α-Conotoxin [S9A]TxID Potently Discriminates between α3β4 and α6/α3β4 Nicotinic Acetylcholine Receptors. Journal of Medicinal Chemistry, 60 13: 5826-5833. doi:10.1021/acs.jmedchem.7b00546


Author Wu, Yong
Zhangsun, Dongting
Zhu, Xiaopeng
Kaas, Quentin
Zhangsun, Manqi
Harvey, Peta J.
Craik, David J.
McIntosh, J. Michael
Luo, Sulan
Title α-Conotoxin [S9A]TxID Potently Discriminates between α3β4 and α6/α3β4 Nicotinic Acetylcholine Receptors
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 1520-4804
0022-2623
Publication date 2017-07-13
Year available 2017
Sub-type Article (original research)
DOI 10.1021/acs.jmedchem.7b00546
Open Access Status Not yet assessed
Volume 60
Issue 13
Start page 5826
End page 5833
Total pages 8
Place of publication Washington, DC United States
Publisher American Chemical Society
Language eng
Subject 1313 Molecular Medicine
3002 Drug Discovery
Abstract 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 ICs > 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.
Formatted abstract
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.
Keyword Norepinephrine Release
Conus-Textile
Antagonist
Discovery
Alpha-6-Beta-4
Dependence
Diversity
Targets
Regiia
Mice
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 41366002
81420108028
81660585
GM103801
GM48677
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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Created: Sun, 06 Aug 2017, 02:00:34 EST by Web Cron on behalf of Institute for Molecular Bioscience