التفاصيل البيبلوغرافية
| العنوان: |
Mechanism of hERG inhibition by gating-modifier toxin, APETx1, deduced by functional characterization |
| المؤلفون: |
Kazuki Matsumura, Takushi Shimomura, Yoshihiro Kubo, Takayuki Oka, Naohiro Kobayashi, Shunsuke Imai, Naomi Yanase, Madoka Akimoto, Masahiro Fukuda, Mariko Yokogawa, Kazuyoshi Ikeda, Jun-ichi Kurita, Yoshifumi Nishimura, Ichio Shimada, Masanori Osawa |
| المصدر: |
BMC Molecular and Cell Biology, Vol 22, Iss 1, Pp 1-16 (2021) |
| بيانات النشر: |
BMC, 2021. |
| سنة النشر: |
2021 |
| المجموعة: |
LCC:Cytology |
| مصطلحات موضوعية: |
Cytology, QH573-671 |
| الوصف: |
Abstract Background Human ether-à-go-go-related gene potassium channel 1 (hERG) is a voltage-gated potassium channel, the voltage-sensing domain (VSD) of which is targeted by a gating-modifier toxin, APETx1. APETx1 is a 42-residue peptide toxin of sea anemone Anthopleura elegantissima and inhibits hERG by stabilizing the resting state. A previous study that conducted cysteine-scanning analysis of hERG identified two residues in the S3-S4 region of the VSD that play important roles in hERG inhibition by APETx1. However, mutational analysis of APETx1 could not be conducted as only natural resources have been available until now. Therefore, it remains unclear where and how APETx1 interacts with the VSD in the resting state. Results We established a method for preparing recombinant APETx1 and determined the NMR structure of the recombinant APETx1, which is structurally equivalent to the natural product. Electrophysiological analyses using wild type and mutants of APETx1 and hERG revealed that their hydrophobic residues, F15, Y32, F33, and L34, in APETx1, and F508 and I521 in hERG, in addition to a previously reported acidic hERG residue, E518, play key roles in the inhibition of hERG by APETx1. Our hypothetical docking models of the APETx1-VSD complex satisfied the results of mutational analysis. Conclusions The present study identified the key residues of APETx1 and hERG that are involved in hERG inhibition by APETx1. These results would help advance understanding of the inhibitory mechanism of APETx1, which could provide a structural basis for designing novel ligands targeting the VSDs of KV channels. |
| نوع الوثيقة: |
article |
| وصف الملف: |
electronic resource |
| اللغة: |
English |
| تدمد: |
2661-8850 |
| Relation: |
https://doaj.org/toc/2661-8850 |
| DOI: |
10.1186/s12860-020-00337-3 |
| URL الوصول: |
https://doaj.org/article/fefcd79f84134514b7e6ed26583065d2 |
| رقم الانضمام: |
edsdoj.fefcd79f84134514b7e6ed26583065d2 |
| قاعدة البيانات: |
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