Chemical Biology of Voltage-Gated Cation Channels

电压门控阳离子通道的化学生物学

• 批准号: 10397069
• 负责人: Christopher A Ahern
• 金额: $ 31.39万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10397069
• 关键词: Adult; Affinity; Agonist; Amino Acids; Animal Model; Attenuated; Binding; Binding Sites; Biology; Biophysics; Calcium; Calcium Channel; Cardiovascular Diseases; Cations; Cells; Chemicals; Chemistry; Chimera organism; Clinical; Communities; Competitive Binding; Complement; Complex; Comprehension; Coupled; Derivation procedure; Development; Dihydropyridines; Drug Antagonism; Drug Targeting; Engineering; Event; Funding; Genetic; Goals; Human; Hydrogen Bonding; Ion Channel; Ion Channel Gating; L-Type Calcium Channels; Magic; Methods; Molecular; Molecular Conformation; Mutagenesis; Neurons; Nifedipine; Pain; Pattern; Peripheral; Pharmaceutical Preparations; Pharmacology; Potassium Channel; Process; Property; Protein Isoforms; Research; Resolution; Role; Shaker potassium channel; Shapes; Side; Signal Transduction; Site; Sodium Channel; Structure; Testing; Therapeutic; antagonist; base; biophysical techniques; clinically relevant; computer studies; conditional knockout; design; improved; inflammatory pain; inhibitor; insight; interdisciplinary approach; interest; knockout animal; member; nanomolar; pain sensation; painful neuropathy; pre-clinical; sensor; tool; unnatural amino acids; voltage; voltage gated channel

Project Summary Voltage-gated ion channels shape electrical signals in excitable cells. There are now high-resolution structures of eukaryotic sodium, potassium and calcium channels, thus providing structural footprint to guide functional hypotheses. In the previous funding period we discovered a dynamic region the pore region of Shaker potassium channels which suggest that state-dependent hydrogen bonding controls the conduction conformation of the channel. These observations have recently been structurally and computationally validated. Further, computational studies indicate that the status of this H-bond network, and thus the conductive state of the channel, are coupled to channel opening at the inner bundle crossing though side-chain to main-chain bonding network along the pore-lining S6 segment. Additionally, voltage gated channels remain high-value pharmacological targets, and the sodium channel Nav1.7 isoform underlies pain sensation. Genetic loss of Nav1.7 abrogates pain sensing in humans, as do adult Nav.17 conditional knock-out animal models. Aryl- and acylsulfonamide compounds target the domain IV (DIV) voltage-sensing domain (VSD) of peripherally expressed sodium channels, such as Nav1.7, with low nanomolar affinity and attenuate inflammatory and neuropathic pain. A structure of the human Nav1.7 DIV VSD in complex with GX-936, a potent arylsulfonamide, suggests that these compounds utilize a unique binding mode whereby the drug simultaneously binds within an aromatic pocket and engages a basic residue (R4) of the activated voltage- sensor. These compounds are useful research tools to advance the understanding of NaV inactivation given the role of the DIV VSD in this process. Further, advancing the chemical details of this drug-bound pose will enable the design of compounds specific activity towards other voltage-sensors. Voltage-gated calcium channels are established drug targets of dihydropyridines (DHP), and recently the binding site was captured in a structure of a bacterial chimeric “CaVAb” – an engineered channel construct with nanomolar DHP binding affinity. However, it is not known if this bacterial chimera faithfully replicated the binding chemistry of the eukaryotic CaV. Not having predictive information on the basis for CaV antagonism severely limits the potential to develop of more critical methods for preclinical screens of therapeutics. The successful execution of these aims will advance the molecular understanding of channel gating and will reveal the binding modes of clinical drugs with high therapeutic value. Further, research tools generated here in will be similarly available to the ion channel research community.

项目摘要 电压门控离子通道在可兴奋细胞中形成电信号。现在有了高分辨率的结构 真核细胞钠、钾和钙通道的结构足迹，从而提供结构足迹来引导功能 假设在上一个资助期，我们发现了一个动态区域，即Shaker的孔隙区域 钾通道，这表明状态依赖性氢键控制传导 通道的构造。这些观测结果最近在结构上和计算上 验证.此外，计算研究表明，这种氢键网络的状态，因此， 通道的导电状态，通过侧链耦合到通道开口处的内束交叉 沿着孔衬S6段沿着主链键合网络。此外，电压门控通道保留 高价值的药理学靶点，钠通道Nav1.7亚型是痛觉的基础。遗传 Nav1.7的缺失消除了人类的疼痛感测，成年Nav.17条件性敲除动物模型也是如此。 芳基-和酰基磺酰胺化合物靶向的结构域IV（DIV）电压敏感结构域（VSD） 外周表达的钠通道，如Nav1.7，具有低纳摩尔亲和力，并减弱 炎性和神经性疼痛。人Nav1.7 DIV VSD与GX-936复合物的结构， 有效的芳基磺酰胺，表明这些化合物利用独特的结合模式， 同时结合在芳族口袋内并接合活化电压的碱性残基（R4）， 传感器.这些化合物是有用的研究工具，以促进对NaV灭活的理解， 在这一过程中，DIV VSD的作用。此外，推进这种药物结合姿势的化学细节将 使得能够设计对其他电压传感器具有特异活性的化合物。电压门控钙 通道是二氢吡啶（DHP）的既定药物靶点，最近， 细菌嵌合体“CaVAb”的结构-具有纳摩尔DHP结合的工程化通道构建体 亲和力然而，尚不清楚这种细菌嵌合体是否忠实地复制了结合化学。 真核CaV。没有基于CaV拮抗作用的预测信息严重限制了 来开发更关键的临床前筛选治疗方法。 这些目标的成功实现将促进对通道门控的分子理解 并将揭示具有较高治疗价值的临床药物的结合模式。此外，研究工具 这里产生的将类似地可用于离子通道研究社区。

项目成果

Introduction: Applying Chemical Biology to Ion Channels.

简介：将化学生物学应用于离子通道。

• DOI: 10.1007/978-1-4939-2845-3_1
• 发表时间: 2015
• 期刊: Advances in experimental medicine and biology
• 作者: Pless,StephanA;Ahern,ChristopherA
• 通讯作者: Ahern,ChristopherA

A rationally designed orthogonal synthetase for genetically encoded fluorescent amino acids.

• DOI: 10.1016/j.heliyon.2020.e05140
• 发表时间: 2020-10
• 期刊: Heliyon
• 影响因子: 4
• 作者: Steinberg X;Galpin J;Nasir G;Sepúlveda RV;Ladron de Guevara E;Gonzalez-Nilo F;Islas LD;Ahern CA;Brauchi SE
• 通讯作者: Brauchi SE

Hydrogen bonds as molecular timers for slow inactivation in voltage-gated potassium channels.

• DOI: 10.7554/elife.01289
• 发表时间: 2013-12-10
• 期刊: eLife
• 影响因子: 7.7
• 作者: Pless SA;Galpin JD;Niciforovic AP;Kurata HT;Ahern CA
• 通讯作者: Ahern CA