A COMBINED COMPUTATIONAL AND EXPERIMENTAL STUDY ON THE LIGAND-GATING IN CNG AND

CNG 和配体门控的综合计算和实验研究

• 批准号: 7601437
• 负责人: Lei Zhou
• 金额: $ 0.03万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7601437
• 关键词: Binding; Cardiovascular system; Cell physiology; Computational Technique; Computer Retrieval of Information on Scientific Projects Database; Computing Methodologies; Coupling; Cyclic AMP; Cyclic GMP; Cyclic Nucleotides; Data; Depth; Funding; Grant; Human; Institution; Intracellular Second Messenger; Ion Channel; Ligand Binding; Ligands; Mediating; Nature; Neuraxis; Play; Protein Kinase; Publishing; Range; Research; Research Personnel; Resources; Role; Second Messenger Systems; Sensory; Source; Structure; Time; Transmembrane Domain; United States National Institutes of Health; cyclic nucleotide-gated cation channel; hyperpolarization-activated cation channel; insight; molecular dynamics; mutant; research study; simulation

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. cAMP and cGMP are two important intracellular second messengers mediating a wide range of cellular processes. Other than direct activating protein kinases, cAMP and cGMP also modulate the function of several types of ion channels through the direct binding to the intracellular cyclic-nucleotide binding domain (CNBD) of the cyclic-nucleotide gated (CNG) and hyperpolarization-activated cation (HCN) channels. These ion channels play important roles in the human sensory, cardiovascular and central nervous systems. Each channel subunit contains a six-transmembrane domain, a CNBD in the C-terminus and a linker region in between. Recently published ion channel related structures have revealed so much mechanistic insights into the channel function. However, the information from a static picture is always limited. Recent advances in computational methodologies and the crystal structure of the CNBD of HCN2 channel make a prefect opportunity to combine the experimental and theoretical approaches to tackle the nature of the ligand-gating in HCN/CNG channels. We are using molecular dynamics and other computational techniques to gain more insights into the ligand binding and the conformational coupling to the channel opening. Preliminary data from molecular dynamics simulation of the CNBD and the electrophysiological characterization of mutant HCN2 channels provided many insights and helped to clarify several important issues. We believe that the allocation of appropriate amount of computational time would facilitate the current simulation projects dramatically and help to obtain a deeper understanding of the ligand-gating in CNG and HCN channels.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 CAMP和cGMP是两个重要的细胞内第二信使，介导着广泛的细胞过程。除了直接激活蛋白激酶，cAMP和cGMP还通过直接与环核苷酸门控(CNG)和超极化激活阳离子(HCN)通道的环核苷酸结合域(CNBD)结合来调节几种类型的离子通道的功能。这些离子通道在人类的感觉、心血管和中枢神经系统中发挥着重要作用。每个通道亚基包含一个六跨膜结构域，在C末端有一个CNBD，在其间有一个连接区。最近发表的离子通道相关结构揭示了对通道功能的许多机械性见解。然而，来自静态图片的信息总是有限的。最近在计算方法和HCN/CNG通道中CNBD的晶体结构方面的进展为将实验和理论相结合来解决HCN/CNG通道中配体门控的性质提供了一个很好的机会。我们正在使用分子动力学和其他计算技术来获得更多关于配体结合和构象耦合到通道开放的见解。CNBD的分子动力学模拟和突变的HCN2通道的电生理特征的初步数据提供了许多见解，并有助于澄清几个重要问题。我们相信，分配适当的计算时间将极大地促进当前的模拟项目，并有助于对CNG和HCN通道中的配体选通有更深入的了解。