Understanding the Molecular Mechanism of Ion and Amino Acid Transport in Neurons

在神经元中，两种跨膜蛋白的功能是必需的：离子通道和转运蛋白。双孔结构域钾通道(K2Ps)是一类参与神经元兴奋性调控的膜蛋白家族，而溶质载体1(SLC1)家族的转运体参与氨基酸摄取。最近，K2P通道(Trek-2)的三维(3D)结构被解决，为离子通道功能的分子机制提供了初步的见解。人们对SLc1转运蛋白的功能知之甚少。DPhil的目的是通过冷冻电子显微镜确定SLC1a转运体的三维结构，并使用已确定的调节剂(例如离子或药物)来研究通道功能。类似地，Trek-2通道的分子机制将使用已知的调节剂和X射线结晶学来阐明。所获得的信息可能有助于通过药物化学设计药理K2P和SLC1调节剂。因此，该项目将涉及生物科学促进健康博士培训伙伴关系(DTP)优先领域。该项目涉及BBSRC系统对生物科学优先事项的方法，因为生物学问题将通过将数据收集与计算建模相结合来回答。BFH、WCUB、ENWW

In neurons, 2 types of transmembrane proteins are required for function: ion channels and transporters. Two-pore domain potassium channels (K2Ps) are a family of membrane proteins involved in the control of neuronal excitability, while transporters of the solute carrier 1 (SLC1) family are involved in amino acid uptake. The 3-dimensional (3D) structures of K2P channel (TREK-2) have recently been solved, providing initial insights into the molecular mechanisms of ion channel function. Much less is known about the function of SLC1 transporters. The aim of this DPhil is to determine the 3D structure of SLC1A transporters by cryo-electron microscopy and to investigate the channel function using identified modulators (e.g. ions or drugs). Similarly, the molecular mechanism of TREK-2 channel will be elucidated using known modulators and X-ray crystallography. The resulting information may be beneficial in the design of pharmacological K2P and SLC1 modulators through medicinal chemistry. Thus, this project will address the Bioscience for Health Doctoral Training Partnerships (DTP) priority area. This project addresses the BBSRC Systems approaches to the biosciences priority, as the biological questions will be answered through integrating data collection with computational modeling. BfH, WCUB, ENWW