Project A

项目A

基本信息

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
项目类别：
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

项目摘要

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.

蛋白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制成，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关键细胞活性。微管在特定时间的组装和拆卸是细胞周期中的重要步骤。这些过程紧密受调节和干扰调节机制可能导致细胞死亡。这些特性使微管蛋白既是生物物理研究的引人入胜的标本，又成为抗癌药物的有用靶标。重要的是要了解微管蛋白分子如何相互相互作用，以及在这些活性中与大量其他蛋白质和配体相互作用，以便对细胞的生命充分了解，并且作为朝这个方向朝着这一方向迈出的第一步，我们确定了通过电子结晶和哭泣的小管蛋白和微管的结构。在拟议的工作中，我们将扩展我们对结构的理解，并了解有关赋予微管蛋白独特特性的过程的更多信息。我们将研究微管蛋白与稳定微管的药物以及与微管结合并利用和调节微管细胞骨架的某些蛋白质的相互作用。这项工作将导致对微管动力学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，更多针对微管蛋白的有效药物。