Project A

项目A

• 批准号: 7925360
• 负责人: KENNETH H DOWNING
• 金额: $ 49.57万
• 依托单位: UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7925360
• 关键词: 3-Dimensional; Address; Affect; Antineoplastic Agents; Binding; Binding Sites; Cell Cycle; Cell Death; Cell Shape; Cell division; Cell physiology; Cells; Cellular biology; Chromosomes; Cilia; Complex; Consensus; Cytoskeleton; Data; Development; Disease; Drug Delivery Systems; Electrons; Epothilone A; Eukaryotic Cell; Flagella; Knowledge; Lead; Learning; Life; Ligands; Maintenance; Malignant Neoplasms; Maps; Medical; Membrane; Microtubule Stabilization; Microtubules; Modeling; Molecular Conformation; Paclitaxel; Parkinson Disease; Pharmaceutical Preparations; Play; Procedures; Process; Property; Protein Binding; Proteins; Regulation; Resolution; Role; Specimen; Structure; Time; Tubulin; Tubulin Interaction; Work; discodermolide; electron crystallography; eleutherobin; fascinate; flexibility; improved; improved functioning; numb protein; organelle movement; parkin gene/protein; protein protein interaction; protein structure; tau Proteins; zampanolide

The protein tubulin plays a vital role in the life of all eukaryotic cells. Microtubules, made mostly of tubulin, are involved in organelle movement, separation of chromosomes during cell division, maintenance of cell shape and other critical cellular activities. The assembly and disassembly of microtubules at particular times are essential steps in the cell cycle. These processes are closely regulated, and interference with the regulatory mechanisms can lead to cell death. These properties have made tubulin both a fascinating specimen for biophysical studies and a useful target for anti-cancer drugs. It is important to understand how tubulin molecules interact with each other as well as with large number of other proteins and ligands in these activities in order to have a full understanding of the life of the cell, and as a first step in this direction we have determined the structure of tubulin and microtubules by electron crystallography and cryo-EM. In the proposed work we will extend our understanding of the structure and learn more about the processes that give tubulin its unique properties. We will study the interaction of tubulin with drugs that stabilize microtubules and the interactions with some of the proteins that bind to microtubules and that utilize and regulate the microtubule cytoskeleton. This work will lead to a rational understanding of the functional mechanisms of microtubule dynamics and may reveal several distinct underlying mechanism of microtubule stabilization, eventually allowing development of new, more effective drugs targeted to tubulin.

微管蛋白在所有真核细胞的生命中起着至关重要的作用。微管主要由微管蛋白组成，参与细胞器运动、细胞分裂过程中染色体的分离、细胞形状的维持和其他重要的细胞活动。微管在特定时间的组装和拆卸是细胞周期中的重要步骤。这些过程密切 调节，干扰调节机制可导致细胞死亡。这些特性使微管蛋白成为生物物理研究的一个有趣的标本，也是抗癌药物的一个有用的靶点。重要的是要了解微管蛋白分子如何相互作用，以及与大量的其他蛋白质和配体在这些活动中，以便有一个全面的了解细胞的生活，并作为在这个方向上的第一步，我们已经确定了微管蛋白和微管的结构，通过电子晶体学和冷冻电镜。在拟议的工作中，我们将扩大我们的结构的理解，并了解更多的过程，使微管蛋白的独特性质。我们将研究微管蛋白与稳定微管的药物的相互作用，以及与一些结合微管并利用和调节微管细胞骨架的蛋白质的相互作用。这项工作将导致对微管动力学的功能机制的合理理解，并可能揭示微管稳定的几种不同的潜在机制，最终允许开发新的，更多的 针对微管蛋白的有效药物。