Understanding Movement and Mechanism in essential Mammalian Membrane Transporters

了解哺乳动物重要膜转运蛋白的运动和机制

• 批准号: 1786308
• 金额: --
• 依托单位: University of East Anglia
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1786308
• 关键词: Understanding; Movement; Mechanism; essential; Mammalian

We study the architecture and functional dynamics of membrane proteins, many medically relevant. Special interest is on large multi-subunit complexes including supercomplexes as well as on transporter systems and their interaction with intra-cellular signalling pathways. There is increasing evidence that membrane proteins do not act alone, but that they are organised as nano-machineries which function through the concerted action of its individual components with high precision and specificity observed in both time and space. We are seeking to unravel the principles underlying the architecture and dynamics of these protein nano-machineries as well as their function and regulation. Our experimental approach focuses on the use of magnetic resonance spectroscopy specifically electron paramagnetic resonance (EPR) and Nuclear Magnetic Resonance (NMR) techniques in combination with molecular biological, and biochemical approaches. In addition advanced molecular dynamics techniques (MD) are used to underpin the experimental observations to provide a dynamic description of function. This project addesses this important theme of transport across biological membrane through the study of a specific bacterial aspartate transporter which is an archaeal homolog of mammalian glutamate transporters, implicated in various neurological diseases including epilepsy and Alzheimer's disease. Recent static crystal structures have suggested large scale conformational changes and we aim to probe the functional dynamics of the protein function using a combination of state-of-the-art magnetic resonance techniques and molecular dynamics simulations.

我们研究膜蛋白的结构和功能动力学，其中许多与医学相关。特别感兴趣的是大型多亚基复合物，包括超级复合物以及转运系统及其与细胞内信号传导途径的相互作用。越来越多的证据表明，膜蛋白并不是单独发挥作用，而是以纳米机械的形式组织起来，通过其各个成分的协同作用发挥作用，在时间和空间上都具有高精度和特异性。我们正在寻求揭示这些蛋白质纳米机器的结构和动力学及其功能和调节的基本原理。我们的实验方法侧重于使用磁共振波谱，特别是电子顺磁共振（EPR）和核磁共振（NMR）技术与分子生物学和生化方法相结合。此外，先进的分子动力学技术（MD）用于支持实验观察，以提供功能的动态描述。该项目通过研究特定的细菌天冬氨酸转运蛋白，强调了跨生物膜转运的这一重要主题，该细菌天冬氨酸转运蛋白是哺乳动物谷氨酸转运蛋白的古菌同源物，与多种神经系统疾病（包括癫痫和阿尔茨海默病）有关。最近的静态晶体结构表明存在大规模的构象变化，我们的目标是结合最先进的磁共振技术和分子动力学模拟来探索蛋白质功能的功能动力学。