• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

大分子Na1.5-K2.1复合物模型

models of the macromolecular Na1.5-K2.1 complex.

作者信息

Stary-Weinzinger Anna

机构信息

Division of Pharmacology and Toxicology, Department of Pharmaceutical Sciences, University of Vienna, Vienna, Austria.

出版信息

Front Physiol. 2024 Feb 26;15:1362964. doi: 10.3389/fphys.2024.1362964. eCollection 2024.

DOI:10.3389/fphys.2024.1362964
PMID:38468705
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10925717/
Abstract

In cardiac cells, the expression of the cardiac voltage-gated Na channel (Na1.5) is reciprocally regulated with the inward rectifying K channel (K2.1). These channels can form macromolecular complexes that pre-assemble early during forward trafficking (transport to the cell membrane). In this study, we present 3D models of Na1.5-K2.1, generated by rigid-body protein-protein docking programs and deep learning-based AlphaFold-Multimer software. Modeling revealed that the two channels could physically interact with each other along the entire transmembrane region. Structural mapping of disease-associated mutations revealed a hotspot at this interface with several trafficking-deficient variants in close proximity. Thus, examining the role of disease-causing variants is important not only in isolated channels but also in the context of macromolecular complexes. These findings may contribute to a better understanding of the life-threatening cardiovascular diseases underlying K2.1 and Na1.5 malfunctions.

摘要

在心肌细胞中，心脏电压门控钠通道（Na1.5）的表达与内向整流钾通道（K2.1）呈反向调节。这些通道可形成大分子复合物，在正向运输（转运至细胞膜）早期预先组装。在本研究中，我们展示了由刚体蛋白质-蛋白质对接程序和基于深度学习的AlphaFold-Multimer软件生成的Na1.5-K2.1三维模型。建模显示，这两种通道可沿整个跨膜区域相互物理作用。疾病相关突变的结构映射揭示了该界面处的一个热点，附近有几个运输缺陷型变体。因此，研究致病变体的作用不仅在孤立通道中很重要，在大分子复合物的背景下也很重要。这些发现可能有助于更好地理解K2.1和Na1.5功能障碍所导致的危及生命的心血管疾病。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7899/10925717/698772f4d3ef/fphys-15-1362964-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7899/10925717/17276bfca908/fphys-15-1362964-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7899/10925717/5bb51f37c588/fphys-15-1362964-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7899/10925717/8b6feef37d4a/fphys-15-1362964-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7899/10925717/698772f4d3ef/fphys-15-1362964-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7899/10925717/17276bfca908/fphys-15-1362964-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7899/10925717/5bb51f37c588/fphys-15-1362964-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7899/10925717/8b6feef37d4a/fphys-15-1362964-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7899/10925717/698772f4d3ef/fphys-15-1362964-g004.jpg

相似文献

1
models of the macromolecular Na1.5-K2.1 complex.大分子Na1.5-K2.1复合物模型
Front Physiol. 2024 Feb 26;15:1362964. doi: 10.3389/fphys.2024.1362964. eCollection 2024.
2
Cardiac Kir2.1 and Na1.5 Channels Traffic Together to the Sarcolemma to Control Excitability.心脏 Kir2.1 和 Na1.5 通道共同转运至肌浆网以控制兴奋性。
Circ Res. 2018 May 25;122(11):1501-1516. doi: 10.1161/CIRCRESAHA.117.311872. Epub 2018 Mar 7.
3
Kir2.1-Na1.5 channelosome and its role in arrhythmias in inheritable cardiac diseases.Kir2.1-Na1.5 通道超分子结构及其在遗传性心脏疾病心律失常中的作用。
Heart Rhythm. 2024 May;21(5):630-646. doi: 10.1016/j.hrthm.2024.01.017. Epub 2024 Jan 18.
4
Protein assemblies of sodium and inward rectifier potassium channels control cardiac excitability and arrhythmogenesis.钠通道和内向整流钾通道的蛋白质组装体控制心脏兴奋性和心律失常的发生。
Am J Physiol Heart Circ Physiol. 2015 Jun 15;308(12):H1463-73. doi: 10.1152/ajpheart.00176.2015. Epub 2015 Apr 10.
5
Kir2.1-Nav1.5 Channel Complexes Are Differently Regulated than Kir2.1 and Nav1.5 Channels Alone.Kir2.1-Nav1.5通道复合体的调控方式与单独的Kir2.1和Nav1.5通道不同。
Front Physiol. 2017 Nov 14;8:903. doi: 10.3389/fphys.2017.00903. eCollection 2017.
6
Brugada syndrome trafficking-defective Nav1.5 channels can trap cardiac Kir2.1/2.2 channels.Brugada 综合征功能缺失型 Nav1.5 通道可捕获心脏 Kir2.1/2.2 通道。
JCI Insight. 2018 Sep 20;3(18). doi: 10.1172/jci.insight.96291.
7
Nav1.5 N-terminal domain binding to α1-syntrophin increases membrane density of human Kir2.1, Kir2.2 and Nav1.5 channels.Nav1.5的N端结构域与α1-肌养蛋白结合可增加人Kir2.1、Kir2.2和Nav1.5通道的膜密度。
Cardiovasc Res. 2016 May 15;110(2):279-90. doi: 10.1093/cvr/cvw009. Epub 2016 Jan 19.
8
Effect of testosterone replacement therapy on cardiac performance and oxidative stress in orchidectomized rats.睾酮替代疗法对去势大鼠心脏功能和氧化应激的影响。
Acta Physiol (Oxf). 2013 Oct;209(2):136-47. doi: 10.1111/apha.12158.
9
Kir2.1 Interactome Mapping Uncovers PKP4 as a Modulator of the Kir2.1-Regulated Inward Rectifier Potassium Currents.Kir2.1 相互作用组图谱揭示 PKP4 作为 Kir2.1 调节内向整流钾电流的调节剂。
Mol Cell Proteomics. 2020 Sep;19(9):1436-1449. doi: 10.1074/mcp.RA120.002071. Epub 2020 Jun 15.
10
Kir2 inward rectification-controlled precise and dynamic balances between Kir2 and HCN currents initiate pacemaking activity.内向整流型钾通道 2（Kir2）的内向整流控制作用精确而动态地平衡 Kir2 和 HCN 电流，从而引发起搏活动。
FASEB J. 2018 Jun;32(6):3047-3057. doi: 10.1096/fj.201701260R. Epub 2018 Jan 12.

引用本文的文献

1
Modular Structure and Polymerization Status of GABA Receptors Illustrated with EM Analysis and AlphaFold2 Prediction.用 EM 分析和 AlphaFold2 预测阐明 GABA 受体的模块化结构和聚合状态。
Int J Mol Sci. 2024 Sep 21;25(18):10142. doi: 10.3390/ijms251810142.

本文引用的文献

1
Voltage sensors of a Na channel dissociate from the pore domain and form inter-channel dimers in the resting state.钠通道的电压传感器在静息状态下与孔域分离，并形成通道间二聚体。
Nat Commun. 2023 Dec 19;14(1):7835. doi: 10.1038/s41467-023-43347-3.
2
Cryo-electron microscopy unveils unique structural features of the human Kir2.1 channel.低温电子显微镜揭示了人类 Kir2.1 通道的独特结构特征。
Sci Adv. 2022 Sep 23;8(38):eabq8489. doi: 10.1126/sciadv.abq8489.
3
Molecular stratification of arrhythmogenic mechanisms in the Andersen Tawil syndrome.
Andersen-Tawil 综合征的心律失常机制的分子分层。
Cardiovasc Res. 2023 May 2;119(4):919-932. doi: 10.1093/cvr/cvac118.
4
Unwinding and spiral sliding of S4 and domain rotation of VSD during the electromechanical coupling in Na1.7.在 Na1.7 的机电耦合过程中，S4 解旋和螺旋滑动以及 VSD 结构域旋转。
Proc Natl Acad Sci U S A. 2022 Aug 16;119(33):e2209164119. doi: 10.1073/pnas.2209164119. Epub 2022 Jul 25.
5
Variable Clinical Appearance of the Kir2.1 Rare Variants in Russian Patients with Long QT Syndrome.俄罗斯长 QT 综合征患者中 Kir2.1 罕见变异的可变临床表型。
Genes (Basel). 2022 Mar 22;13(4):559. doi: 10.3390/genes13040559.
6
Inwardly Rectifying Potassium Channel Kir2.1 and its "Kir-ious" Regulation by Protein Trafficking and Roles in Development and Disease.内向整流钾通道Kir2.1及其通过蛋白质转运的“奇特”调控以及在发育和疾病中的作用
Front Cell Dev Biol. 2022 Feb 9;9:796136. doi: 10.3389/fcell.2021.796136. eCollection 2021.
7
Kir Channel Molecular Physiology, Pharmacology, and Therapeutic Implications.Kir 通道的分子生理学、药理学及治疗学意义。
Handb Exp Pharmacol. 2021;267:277-356. doi: 10.1007/164_2021_501.
8
Cardiac potassium inward rectifier Kir2: Review of structure, regulation, pharmacology, and arrhythmogenesis.心脏钾离子内向整流通道 Kir2：结构、调节、药理学和心律失常发生机制的综述。
Heart Rhythm. 2021 Aug;18(8):1423-1434. doi: 10.1016/j.hrthm.2021.04.008. Epub 2021 Apr 20.
9
Structural Pharmacology of Voltage-Gated Sodium Channels.电压门控钠离子通道的结构药理学。
J Mol Biol. 2021 Aug 20;433(17):166967. doi: 10.1016/j.jmb.2021.166967. Epub 2021 Mar 29.
10
Comparative structural analysis of human Na1.1 and Na1.5 reveals mutational hotspots for sodium channelopathies.比较人源 Na1.1 和 Na1.5 钠离子通道的结构分析揭示钠离子通道病的突变热点。
Proc Natl Acad Sci U S A. 2021 Mar 16;118(11). doi: 10.1073/pnas.2100066118.