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Loop2 Size Modification Reveals Significant Impacts on the Potency of α-Conotoxin TxID

α4/6-conotoxin TxID, which was identified from Conus textile, simultaneously blocks rat (r) α3β4 and rα6/α3β4 nicotinic acetylcholine receptors (nAChRs) with IC(50) values of 3.6 nM and 33.9 nM, respectively. In order to identify the effects of loop2 size on the potency of TxID, alanine (Ala) insert...

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Autores principales: Dong, Jianying, Zhang, Panpan, Xie, Junjie, Xie, Ting, Zhu, Xiaopeng, Zhangsun, Dongting, Yu, Jinpeng, Luo, Sulan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10222858/
https://www.ncbi.nlm.nih.gov/pubmed/37233480
http://dx.doi.org/10.3390/md21050286
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author Dong, Jianying
Zhang, Panpan
Xie, Junjie
Xie, Ting
Zhu, Xiaopeng
Zhangsun, Dongting
Yu, Jinpeng
Luo, Sulan
author_facet Dong, Jianying
Zhang, Panpan
Xie, Junjie
Xie, Ting
Zhu, Xiaopeng
Zhangsun, Dongting
Yu, Jinpeng
Luo, Sulan
author_sort Dong, Jianying
collection PubMed
description α4/6-conotoxin TxID, which was identified from Conus textile, simultaneously blocks rat (r) α3β4 and rα6/α3β4 nicotinic acetylcholine receptors (nAChRs) with IC(50) values of 3.6 nM and 33.9 nM, respectively. In order to identify the effects of loop2 size on the potency of TxID, alanine (Ala) insertion and truncation mutants were designed and synthesized in this study. An electrophysiological assay was used to evaluate the activity of TxID and its loop2-modified mutants. The results showed that the inhibition of 4/7-subfamily mutants [+9A]TxID, [+10A]TxID, [+14A]TxID, and all the 4/5-subfamily mutants against rα3β4 and rα6/α3β4 nAChRs decreased. Overall, ala-insertion or truncation of the 9th, 10th, and 11th amino acid results in a loss of inhibition and the truncation of loop2 has more obvious impacts on its functions. Our findings have strengthened the understanding of α-conotoxin, provided guidance for further modifications, and offered a perspective for future studies on the molecular mechanism of the interaction between α-conotoxins and nAChRs.
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spelling pubmed-102228582023-05-28 Loop2 Size Modification Reveals Significant Impacts on the Potency of α-Conotoxin TxID Dong, Jianying Zhang, Panpan Xie, Junjie Xie, Ting Zhu, Xiaopeng Zhangsun, Dongting Yu, Jinpeng Luo, Sulan Mar Drugs Article α4/6-conotoxin TxID, which was identified from Conus textile, simultaneously blocks rat (r) α3β4 and rα6/α3β4 nicotinic acetylcholine receptors (nAChRs) with IC(50) values of 3.6 nM and 33.9 nM, respectively. In order to identify the effects of loop2 size on the potency of TxID, alanine (Ala) insertion and truncation mutants were designed and synthesized in this study. An electrophysiological assay was used to evaluate the activity of TxID and its loop2-modified mutants. The results showed that the inhibition of 4/7-subfamily mutants [+9A]TxID, [+10A]TxID, [+14A]TxID, and all the 4/5-subfamily mutants against rα3β4 and rα6/α3β4 nAChRs decreased. Overall, ala-insertion or truncation of the 9th, 10th, and 11th amino acid results in a loss of inhibition and the truncation of loop2 has more obvious impacts on its functions. Our findings have strengthened the understanding of α-conotoxin, provided guidance for further modifications, and offered a perspective for future studies on the molecular mechanism of the interaction between α-conotoxins and nAChRs. MDPI 2023-05-01 /pmc/articles/PMC10222858/ /pubmed/37233480 http://dx.doi.org/10.3390/md21050286 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Dong, Jianying
Zhang, Panpan
Xie, Junjie
Xie, Ting
Zhu, Xiaopeng
Zhangsun, Dongting
Yu, Jinpeng
Luo, Sulan
Loop2 Size Modification Reveals Significant Impacts on the Potency of α-Conotoxin TxID
title Loop2 Size Modification Reveals Significant Impacts on the Potency of α-Conotoxin TxID
title_full Loop2 Size Modification Reveals Significant Impacts on the Potency of α-Conotoxin TxID
title_fullStr Loop2 Size Modification Reveals Significant Impacts on the Potency of α-Conotoxin TxID
title_full_unstemmed Loop2 Size Modification Reveals Significant Impacts on the Potency of α-Conotoxin TxID
title_short Loop2 Size Modification Reveals Significant Impacts on the Potency of α-Conotoxin TxID
title_sort loop2 size modification reveals significant impacts on the potency of α-conotoxin txid
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10222858/
https://www.ncbi.nlm.nih.gov/pubmed/37233480
http://dx.doi.org/10.3390/md21050286
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