Structural Determinants of the Biological Activity of Ryanodine

瑞尼定生物活性的结构决定因素

• 批准号: 9317684
• 负责人: William Welch
• 金额: $ 37.58万
• 依托单位: Board of Regents, NSHE, obo University of Nevada, Reno
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-03-15 至 1998-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=9317684&HistoricalAwards=false
• 关键词: Structural; Determinants; Biological; Activity; Ryanodine

9317684 Welch Ryanodine is a plant alkaloid which binds to a specific receptor,an intracellular calcium release channel, first identified at the triad junction of skeletal muscle. Subsequently, ryanodine receptors (RyR) have been found in many non-muscle cells including cells of the central nervous system. Ryanodine has been shown to be a powerful effector of calcium regulation in muscle. Although the ryanodine molecule is complex, important stearic and electrostatic interactions can be localized to relatively small, specific regions of the molecule. The overall goal of this project is to elucidate the relationship between ligand structure and the biological activities of the ryanoids. The aims are to (1) develop biologically active ryanoids with minimal structure, (2) develop agents which effect specific alterations in RyR properties, (3)define the mammalian skeletal muscle ryanodine binding site, (4)lay the groundwork for development of RyR isoform-specific agents and (5) define endogenous effectors. This project will focus on rabbit skeletal muscle RyR. Approaches will be: (I) New ryanodine analogs will be developed. (II) The biological activity of these compounds will be assessed by measurements of ligand binding to the RyR, the modulation of ion channel activity of the RyR using ionic flux and planar lipid bilayer single channel measurements, and functional effects on intact cells. (III) The conformations of the ryanoids will be deduced from the covalent structures by molecular mechanics, molecular dynamics and quantum mechanics. The deduced conformations will be compared to NMR or crystallographic data whenever possible (for example, the X-ray and NMR structures of ryanodine have been solved). A comparative molecular field analysis (ComFA) will be produced for selected analogs, and correlations between the stearic and electrostatic fields computed to discern the relationship between the biological activities and the structure of the ryanodine a nalogs. (IV) The results of the CoMFA will be used to design new ryanoids for testing, refinement and correction of hypotheses. %%% Calcium ion regulates many critical cellular functions such as muscle contraction. The levels of calcium free in cells are precisely regulated by physiological control mechanisms. Ryanodine is a plant alkaloid which has a powerful effect on calcium regulation in cells and can serve as a useful tool in studying calcium control mechanisms. Ryanodine acts by binding to a specific receptor, an intracellular calcium release channel. Ryanodine receptors were first identified in skeletal muscle, but have also been found in many non-muscle cells including cells of the central nervous system. Although the ryanodine molecule is complex, its functional interactions with its receptor can be localized to relatively small, specific regions of the molecule. The overall goal of this project is to elucidate the relationship between the structure and the biological activities of the ryanoids. This will result in the development of important new probes which will enhance our understanding of cellular calcium regulation. ***

小行星9317684 Ryanodine是一种植物生物碱，它与一种特异性受体结合，这种受体是一种细胞内钙释放通道，首先在骨骼肌的三联体连接处发现。 随后，在许多非肌肉细胞包括中枢神经系统细胞中发现了兰尼碱受体（RyR）。 Ryanodine已被证明是肌肉中钙调节的有力效应物。 虽然兰尼定分子很复杂，但重要的硬脂酸和静电相互作用可以局限于分子的相对较小的特定区域。 本研究的主要目的是阐明类ryanoids的配体结构与生物活性之间的关系。 目的是（1）开发具有最小结构的生物活性类ryanoids，（2）开发影响RyR特性特异性改变的药物，（3）确定哺乳动物骨骼肌ryanodine结合位点，（4）为开发RyR亚型特异性药物奠定基础，（5）确定内源性效应物。 本项目将重点关注兔骨骼肌RyR。 研究的途径是：（1）开发新的兰尼碱类似物。 (II)这些化合物的生物活性将通过测量与RyR的配体结合、使用离子通量和平面脂质双层单通道测量对RyR的离子通道活性的调节以及对完整细胞的功能效应来评估。 (III)利用分子力学、分子动力学和量子力学的方法，从共价结构推导出类ryanoids的构象。 尽可能将推导的构象与NMR或晶体学数据进行比较（例如，ryanodine的X射线和NMR结构已经解决）。 比较分子场分析（ComFA）将产生选定的类似物，并计算硬脂和静电场之间的相关性，以辨别生物活性和结构的ryanodine a nalogs之间的关系。 (IV)CoMFA的结果将用于设计新的ryanoids，用于测试，改进和校正假设。 %钙离子调节许多重要的细胞功能，如肌肉收缩。 细胞中游离钙的水平由生理控制机制精确调节。 Ryanodine是一种植物生物碱，对细胞内钙离子的调节有很强的作用，可以作为研究钙离子的有用工具。 钙控制机制Ryanodine通过与一种特异性受体（细胞内钙释放通道）结合发挥作用。 Ryanodine受体首先在骨骼肌中发现，但也在许多非肌肉细胞中发现，包括中枢神经系统细胞。 尽管兰尼定分子很复杂，但其与受体的功能性相互作用可以定位于分子的相对较小的特定区域。 本项目的总体目标是阐明ryanoids的结构和生物活性之间的关系。 这将导致重要的新探针的开发，这将提高我们对细胞钙调节的理解。 ***