Structural Modeling of Brain Sodium and Calcium Channels

脑钠通道和钙通道的结构建模

• 批准号: 7217547
• 负责人: VLADIMIR M YAROV-YAROVOY
• 金额: $ 12.09万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7217547
• 关键词: Action Potentials; Algorithms; Base of the Brain; Behavior; Biochemistry; Biophysics; Brain; Calcium Channel; Complement; Computational Biology; Computer Simulation; Computing Methodologies; Doctor of Philosophy; Drug Interactions; Emotions; Gated Ion Channel; Goals; Informatics; Integral Membrane Protein; Ion Channel; Knowledge; Lead; Learning; Membrane; Membrane Proteins; Memory; Mentored Research Scientist Development Award; Mentorship; Methods; Modeling; Molecular; Molecular Biology; Muscle Cells; Nerve; Neurons; Neurosciences; Neurotoxins; Peptides; Personal Satisfaction; Pharmaceutical Preparations; Phosphorylation; Physics; Physiological; Proteins; Rate; Regulation; Research; Research Personnel; Second Messenger Systems; Site-Directed Mutagenesis; Sodium; Sodium Channel; Structural Models; Structure; Structure-Activity Relationship; Synaptic Transmission; Techniques; Testing; Training; Universities; Washington; Work; base; computer program; computerized tools; experience; fundamental research; insight; interest; neuroinformatics; novel; protein structure; research study; second messenger; success; three-dimensional modeling; voltage

DESCRIPTION (provided by applicant): This proposal is a request for a Mentored Research Scientist Development Award (K01) for senior fellow researcher Dr. Vladimir Yarov-Yarovoy. The candidate holds advanced degrees in Physics (M.S.) and Biochemistry and Molecular Biology (Ph.D.) and is well trained in the field of Neuroscience. The candidate's ultimate goal is to lead an independent research group, which will conduct fundamental research in the field of neuroinformatics - the interdisciplinary field that bridges research in neuroscience with that in informatics. Successful completion of this proposal will further enhance the candidate's expertise in the field of neuroscience and also will allow him to develop the essential theoretical knowledge and experience in the field of informatics. The candidate's long-term research interests include structure function studies of neuronal ion channels and computational modeling of protein structure, protein-protein, and protein-drug interactions. Dr. Yarov-Yarovoy's training will consist of computational biology and computer programming courses and research work under the dual mentorship of Drs. William Catterall and David Baker. Dr. Catterall is an accomplished investigator in studying the structure and function of the brain voltage-gated sodium and calcium channels. Dr. Baker is an accomplished investigator in predicting the three-dimensional protein structure using novel computational methods. The goal of the project is to develop three-dimensional models of the brain voltage-gated sodium and calcium channels. These models will provide key structural information on the molecular basis of the brain sodium and calcium channel gating, their modulation by second messenger-activated protein phosphorylation and by peptide neurotoxins, and their interaction with therapeutically useful pore-blocking drugs. The novel features of the models will be experimentally tested using site-directed mutagenesis and electrophysiological techniques. The novel computational tools developed in this project will be generalized for structure prediction of other ion channels. Finally, understanding the brain sodium and calcium channel function and modulation on the structural level will lead to a better understanding of mechanisms of neuromodulation, which in turn will give us profound insights into the fundamental mechanisms underlying learning, memory, emotion and behavior.

描述（由申请人提供）：本提案是为高级研究员 Vladimir Yarov-Yarovoy 博士申请指导研究科学家发展奖 (K01)。该候选人拥有物理学（硕士）和生物化学和分子生物学（博士学位）的高级学位，并在神经科学领域接受过良好的培训。候选人的最终目标是领导一个独立的研究小组，该小组将在神经信息学领域进行基础研究，神经信息学是连接神经科学与信息学研究的跨学科领域。该提案的成功完成将进一步增强候选人在神经科学领域的专业知识，也将使他能够发展信息学领域的必要理论知识和经验。该候选人的长期研究兴趣包括神经元离子通道的结构功能研究以及蛋白质结构、蛋白质-蛋白质和蛋白质-药物相互作用的计算模型。 Yarov-Yarovoy 博士的培训将包括计算生物学和计算机编程课程以及在 Dr. Yarov-Yarovoy 博士的双重指导下进行研究工作。威廉·卡特罗尔和大卫·贝克。 Catterall 博士是一位在研究大脑电压门控钠通道和钙通道的结构和功能方面颇有造诣的研究者。 Baker 博士是一位在使用新颖的计算方法预测三维蛋白质结构方面颇有造诣的研究者。 该项目的目标是开发大脑电压门控钠通道和钙通道的三维模型。这些模型将提供有关脑钠通道和钙通道门控的分子基础、第二信使激活蛋白磷酸化和肽神经毒素的调节以及它们与治疗上有用的孔阻塞药物的相互作用的关键结构信息。该模型的新颖特征将使用定点诱变和电生理学技术进行实验测试。该项目开发的新型计算工具将推广用于其他离子通道的结构预测。最后，了解大脑钠通道和钙通道的功能和结构水平上的调节将有助于更好地理解神经调节机制，从而使我们深入了解学习、记忆、情感和行为的基本机制。

项目成果

Structural refinement of the hERG1 pore and voltage-sensing domains with ROSETTA-membrane and molecular dynamics simulations.

• DOI: 10.1002/prot.22815
• 发表时间: 2010-11-01
• 期刊: PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
• 影响因子: 2.9
• 作者: Subbotina, Julia;Yarov-Yarovoy, Vladimir;Lees-Miller, James;Durdagi, Serdar;Guo, Jiqing;Duff, Henry J.;Noskov, Sergei Yu.
• 通讯作者: Noskov, Sergei Yu.