SELECTIVITY AND MECHANISM OF ACTION OF IONOPHORES

离子载体的选择性和作用机制

• 批准号: 3432777
• 负责人: WILLIAM L DUAX
• 金额: $ 2.7万
• 依托单位: HAUPTMAN-WOODWARD MEDICAL RESEARCH INST
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-30 至 1996-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3432777
• 关键词: X ray crystallography; chelating agents; chemical structure function; conformation; crystallization; data collection; ion transport; ionophores; membrane channels; stereochemistry; valine

The goal of this research project is to elucidate the structural principles of ion transport and to establish the main stereochemical criteria which are necessary for construction of shuttle carriers and channels with specified ion selectivity, binding and conducting properties. The chemical and geometric features which characterize ion selective organic transport ligands are to be examined in greater detaiL The efficient transport of ions does not simply depend on a high binding affinity of channel or shuttle ligands for specific ions at the solvent/lipid interface of the ion-rich side of the membrane, but also on a facilitated mechanism of ion release on the distal side of the membrane which permits the channel or the ligand shuttle to eject an ion so it can recycle back to the ion-rich side of the membrane. The series of newly synthesized valinomycin, cyclo-[D-Val-L-Lac-L-Val-D- Hyi)3-], analogues are to be examined to test a number of hypotheses concerning the flexibility with which the uncomplexed ionophore may wrap around and chelate metals of different atomic radii and ionic charge. This series includes six (DLLD)3 stereoregular cyclo-dodecadepsipeptide analogues which substitute Gly for D-Val and L-Ala, L-Pro, L-Glu or L- Glu(OBzlNO2) for L-Val in various single or multiple position sites of the normal valinomycin sequence. One unusually interesting analogue which has an (LLLD)-(DLDD)(DLLD) altered stereoregular sequence of valine and hydroxyisovaleric acid residues is also to be investigated. These ligand analogues are to be crystallized in the uncomplexed form as well as complexed with various sized and charged ions in different chemical solvents. Studies of the channel forming ionophore gramicidin A in free and various complexed forms with alkaline cations will be expanded to new crystal forms obtained from different pure solvents and their mixtures. Different polymorphs of all compounds under study will be extensively examined by X-ray diffraction, molecular mechanics and computer graphics methods to explore the conformational space of these agents for elucidation of the molecular mechanism of their functioning and design new analogs with predetermined properties.

这项研究项目的目的是阐明结构 离子传输原理和建立立体化学的主要方法 建造穿梭运输船所必需的标准和 具有特定离子选择性、结合和导电性的通道 属性。离子的化学和几何特征 选择性有机运输配体将被更详细地研究 离子的有效传输不是简单地依赖于高结合 通道或穿梭配体对特定离子的亲和力 溶剂/脂质界面的离子富集面，也就是膜上 一种促进膜远端离子释放的机制 它允许通道或配体穿梭排出离子，因此它可以 循环回到膜富含离子的一侧。 新合成的呋喃霉素系列，环-[D-Val-L-Lac-L-Val-D- Hyi)3-]，类似物将被检验以检验一些假说 关于未络合的离子载体可以包裹的灵活性 围绕不同原子半径和离子电荷的金属并将其络合。这 系列包括六个(DLLD)3立体规则环十二肽 用甘氨酸代替D-Val和L-丙氨酸、L-Pro、L-Glu或L的类似物- 谷氨酸(OBzlNO2)对L-Val的影响 正常的呋喃霉素序列。一个异常有趣的类比，它有 (LLLD)-(DLDD)(DLLD)改变的Valine和DLLD的立体规则序列 羟基异戊酸残留量也有待调查。这些配基 类似物应以不络合的形式结晶，以及 在不同的化学物质中与不同大小和带电的离子络合 溶剂。 游离态和不同态离子载体甘草素A形成通道的研究 与碱性阳离子的络合形式将扩展成新的晶体 从不同的纯溶剂及其混合物中获得的形式。 所有正在研究的化合物的不同晶型将被广泛地 经X射线衍射法、分子力学和计算机图形学检验 方法探索这些试剂的构象空间 阐明其作用的分子机制并设计新的 具有预定性质的类似物。