Structure and Function of Voltage-Gated Ion Channels and their Applications for Rational Drug Design

电压门控离子通道的结构和功能及其在合理药物设计中的应用

• 批准号: BB/L006790/1
• 负责人: Bonnie Wallace
• 金额: $ 67.84万
• 依托单位: Birkbeck, University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL006790%2F1
• 关键词: Structure; Function; Voltage; Gated; Ion

Sodium channels are membrane proteins which enable the regulation and flow of sodium ions across cell membranes. They are found in all eukaryotic organisms and a range of bacteria. In humans they exhibit a wide range of functions in the healthy organism, and are the targets for many pharmaceutical drugs for treatment of neurological and cardiac diseases. In insects they are the target sites of many insecticides, and also the source of development of resistance. This proposal is to determine the crystal structures of a number of natural and mutant sodium channels and related ion channels, and compare their structures with functional studies to better understand the means by which the channels open and close and selectively translocate sodium ions. By examining complexes of these channels with actual and potential drugs and ligands, this should enhance the rational development of new and highly specific insecticides and pharmaceuticals.

钠通道是一种膜蛋白，能够调节钠离子穿过细胞膜的流动。它们存在于所有真核生物和一系列细菌中。在人类中，它们在健康生物体中表现出广泛的功能，并且是用于治疗神经和心脏疾病的许多药物的靶标。在昆虫中，它们是许多杀虫剂的靶位点，也是抗性发展的来源。本提案旨在确定一些天然和突变钠通道及相关离子通道的晶体结构，并将其结构与功能研究进行比较，以更好地了解通道打开和关闭以及选择性转运钠离子的方式。通过研究这些通道与实际和潜在的药物和配体的复合物，这将促进新的和高度特异性的杀虫剂和药物的合理开发。

项目成果

Tamoxifen complexes with the voltage-gated sodium channel reveal novel drug binding sites

他莫昔芬与电压门控钠通道的复合物揭示了新的药物结合位点

• DOI: 10.1016/j.bpj.2021.11.2583
• 发表时间: 2022
• 期刊: Biophysical Journal
• 影响因子: 3.4
• 作者: Hollingworth D

Thermal melt circular dichroism spectroscopic studies for identifying stabilising amphipathic molecules for the voltage-gated sodium channel NavMs.

• DOI: 10.1002/bip.23067
• 发表时间: 2018-08
• 期刊: Biopolymers
• 影响因子: 2.9
• 作者: Ireland SM;Sula A;Wallace BA
• 通讯作者: Wallace BA

Voltage-gated sodium channels as targets for pyrethroid insecticides.

• DOI: 10.1007/s00249-016-1195-1
• 发表时间: 2017-10
• 期刊: European biophysics journal : EBJ
• 作者: Field LM;Emyr Davies TG;O'Reilly AO;Williamson MS;Wallace BA
• 通讯作者: Wallace BA

Molecular Dynamics Simulations of the Open State Structure of a Bacterial Voltage-Gated Sodium Channel Reveal the Binding Mechanisms of Channel Blockers

细菌电压门控钠通道开放态结构的分子动力学模拟揭示了通道阻断剂的结合机制

• 发表时间: 2016
• 期刊: BIOPHYSICAL JOURNAL
• 影响因子: 3.4
• 作者: Ke Song

Lipid binding attenuates channel closure of the outer membrane protein OmpF.

• DOI: 10.1073/pnas.1721152115
• 发表时间: 2018-06-26
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Liko I;Degiacomi MT;Lee S;Newport TD;Gault J;Reading E;Hopper JTS;Housden NG;White P;Colledge M;Sula A;Wallace BA;Kleanthous C;Stansfeld PJ;Bayley H;Benesch JLP;Allison TM;Robinson CV
• 通讯作者: Robinson CV