Understanding Movement and Mechanism in essential Mammalian Membrane Transporters

我们研究膜蛋白的结构和功能动力学，许多医学相关。特别感兴趣的是大型多亚基复合物，包括超复合物以及转运体系统及其与细胞内信号通路的相互作用。越来越多的证据表明，膜蛋白不是单独起作用的，而是作为纳米机器组织起来的，通过其各个组成部分的协同作用，在时间和空间上都能观察到高精度和特异性。我们正在寻求揭开这些蛋白质纳米机器的结构和动力学的基本原理，以及它们的功能和调节。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，结合分子生物学和生物化学方法。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。该项目通过研究一种特定的细菌谷氨酸转运体来解决跨生物膜运输的重要主题，该转运体是哺乳动物谷氨酸转运体的古细菌同源物，与包括癫痫和阿尔茨海默病在内的各种神经系统疾病有关。最近的静态晶体结构表明了大规模的构象变化，我们的目标是利用最先进的磁共振技术和分子动力学模拟的结合来探测蛋白质功能的功能动力学。

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.