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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 cAMP和CGMP是两个重要的细胞内第二使者，介导了广泛的细胞过程。除直接激活蛋白激酶外，CAMP和CGMP还通过直接结合与环状核苷酸门（CNG）和超极化激活阳离子（HCN）通道的细胞内环核苷酸结合结构域（CNBD）的直接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感觉，心血管和中枢神经系统中起着重要作用。每个通道亚基都包含一个六跨膜结构域，C-terminus中的CNBD和两者之间的接头区域。最近发表的离子通道相关结构揭示了对通道功能的大量机械见解。但是，静态图片中的信息始终受到限制。 HCN2通道的CNBD的计算方法和CNBD的晶体结构的最新进展为结合了实验和理论方法，以解决HCN/CNG通道中配体门控的性质。我们正在使用分子动力学和其他计算技术来获得更多的见解，并与配体结合以及与通道开口的构象耦合。来自CNBD的分子动力学模拟的初步数据和突变HCN2通道的电生理表征提供了许多见解，并有助于阐明几个重要问题。我们认为，分配适当的计算时间将有助于当前的模拟项目，并有助于更深入地了解CNG和HCN渠道中的配体门控。