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Open conformation of hERG channel turrets revealed by a specific scorpion toxin BmKKx2
BACKGROUND: The human ether-a-go-go-related gene potassium channel (hERG) has an unusual long turret, whose role in recognizing scorpion toxins remains controversial. Here, BmKKx2, the first specific blocker of hERG channel derived from scorpion Mesobuthus martensii, was identified and the turret ro...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4108063/ https://www.ncbi.nlm.nih.gov/pubmed/24725272 http://dx.doi.org/10.1186/2045-3701-4-18 |
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author | Hu, You-Tian Hu, Jun Li, Tian Wei, Jing-Jing Feng, Jing Du, Yi-Mei Cao, Zhi-Jian Li, Wen-Xin Wu, Ying-Liang |
author_facet | Hu, You-Tian Hu, Jun Li, Tian Wei, Jing-Jing Feng, Jing Du, Yi-Mei Cao, Zhi-Jian Li, Wen-Xin Wu, Ying-Liang |
author_sort | Hu, You-Tian |
collection | PubMed |
description | BACKGROUND: The human ether-a-go-go-related gene potassium channel (hERG) has an unusual long turret, whose role in recognizing scorpion toxins remains controversial. Here, BmKKx2, the first specific blocker of hERG channel derived from scorpion Mesobuthus martensii, was identified and the turret role of hERG channel was re-investigated using BmKKx2 as a molecular probe. RESULTS: BmKKx2 was found to block hERG channel with an IC(50) of 6.7 ± 1.7 nM and share similar functional surface with the known hERG channel inhibitor BeKm-1. The alanine-scanning mutagenesis data indicate that different residue substitutions on hERG channel by alanine decreased the affinities of toxin BmKKx2 by about 10-fold compared with that of wild-type hERG channel, which reveals that channel turrets play a secondary role in toxin binding. Different from channel turret, the pore region of hERG channel was found to exert the conserved and essential function for toxin binding because the mutant hERG-S631A channel remarkably decreased toxin BmKKx2 affinity by about 104-fold. CONCLUSIONS: Our results not only revealed that channel turrets of hERG channel formed an open conformation in scorpion toxin binding, but also enriched the diversity of structure-function relationships among the different potassium channel turrets. |
format | Online Article Text |
id | pubmed-4108063 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-41080632014-08-04 Open conformation of hERG channel turrets revealed by a specific scorpion toxin BmKKx2 Hu, You-Tian Hu, Jun Li, Tian Wei, Jing-Jing Feng, Jing Du, Yi-Mei Cao, Zhi-Jian Li, Wen-Xin Wu, Ying-Liang Cell Biosci Research BACKGROUND: The human ether-a-go-go-related gene potassium channel (hERG) has an unusual long turret, whose role in recognizing scorpion toxins remains controversial. Here, BmKKx2, the first specific blocker of hERG channel derived from scorpion Mesobuthus martensii, was identified and the turret role of hERG channel was re-investigated using BmKKx2 as a molecular probe. RESULTS: BmKKx2 was found to block hERG channel with an IC(50) of 6.7 ± 1.7 nM and share similar functional surface with the known hERG channel inhibitor BeKm-1. The alanine-scanning mutagenesis data indicate that different residue substitutions on hERG channel by alanine decreased the affinities of toxin BmKKx2 by about 10-fold compared with that of wild-type hERG channel, which reveals that channel turrets play a secondary role in toxin binding. Different from channel turret, the pore region of hERG channel was found to exert the conserved and essential function for toxin binding because the mutant hERG-S631A channel remarkably decreased toxin BmKKx2 affinity by about 104-fold. CONCLUSIONS: Our results not only revealed that channel turrets of hERG channel formed an open conformation in scorpion toxin binding, but also enriched the diversity of structure-function relationships among the different potassium channel turrets. BioMed Central 2014-04-11 /pmc/articles/PMC4108063/ /pubmed/24725272 http://dx.doi.org/10.1186/2045-3701-4-18 Text en Copyright © 2014 Hu et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Hu, You-Tian Hu, Jun Li, Tian Wei, Jing-Jing Feng, Jing Du, Yi-Mei Cao, Zhi-Jian Li, Wen-Xin Wu, Ying-Liang Open conformation of hERG channel turrets revealed by a specific scorpion toxin BmKKx2 |
title | Open conformation of hERG channel turrets revealed by a specific scorpion toxin BmKKx2 |
title_full | Open conformation of hERG channel turrets revealed by a specific scorpion toxin BmKKx2 |
title_fullStr | Open conformation of hERG channel turrets revealed by a specific scorpion toxin BmKKx2 |
title_full_unstemmed | Open conformation of hERG channel turrets revealed by a specific scorpion toxin BmKKx2 |
title_short | Open conformation of hERG channel turrets revealed by a specific scorpion toxin BmKKx2 |
title_sort | open conformation of herg channel turrets revealed by a specific scorpion toxin bmkkx2 |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4108063/ https://www.ncbi.nlm.nih.gov/pubmed/24725272 http://dx.doi.org/10.1186/2045-3701-4-18 |
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