Replacement of essential core instrument that can no longer be supported for service contract

本项目旨在确定电压感应域如何控制离子通道门控， 对所有神经元传递、对控制内溶酶体递送到细胞中以及对神经元的再循环至关重要。 将膜蛋白释放到质膜上。其目的是确定所产生的运动 在电压感测域中，基于静息状态的第一原子结构和 激活状态在同一个通道，一个内溶酶体双孔通道。目的是确定这是如何 电压变化引起的结构变化通过分离共价键而被传递到门控中心通道 通过直接的蛋白质序列，从传感器和 频道。该方法使用不同的双孔通道，化学交联，化学捕集， 突变耦合到通道记录，其次是原子结构定义的中间状态， 过程利用相关蛋白质，目的是可视化与粘脂相关的细胞复合物， 内溶酶体这些伙伴关系影响许多溶酶体和神经元疾病，并提供了一个地图， 这些过程的抑制剂的设计，将导致药物， 优势的内溶酶体中通道的相互作用组提供了一个惊人的连接网络 对于本提案主题的疾病。第二个目标是如何跨膜 转运蛋白对细胞活力至关重要，将必需的营养物质转运到细胞中，并在分子水平上发挥作用。 结构层面。通过原子结构测定必需磷酸盐的转运蛋白，以及 必需葡萄糖和尿酸，这些转运蛋白提供了一个路线图，以针对这些过程， 抑制剂和活化剂，其将在癌症中具有治疗优势，并且用于调节 细胞中的“主”调节器。

This project seeks to determine how voltage sensing domains control ion channel gating, a process fundamental to all neuronal transmission, to control of endolysosomal delivery into cells, and recycling of membrane proteins out to the plasma membrane. The aim is to determine the motion that is brought about in voltage sensing domains upon activation based on the first atomic structures of a resting state and an activated state in the same channel, an endolysosomal two-pore channel. The aim is to determine how this structural change evoked upon voltage change is relayed to gate a central channel, by separating covalent attachment by means of a direct protein sequence, from non-covalent interactions between the sensor and the channel. The approach uses different two-pore channels, chemical cross linking, chemical trapping, and mutations coupled to channel recordings, followed by atomic structural definition of intermediate states in the process. With a related protein the aim is to visualize cellular complexes that associate with mucolipin in the endolysosome. These partnerships impact many lysosomal and neuronal diseases and offer a map for design of inhibitors of these processes that will lead the way to drugs that can be therapeutically advantageous. The interactome of channels in the endolysosome offer an amazing network of connections to disease that are a subject of this proposal. A second set of aims concerns how transmembrane transporters, crucial to cell viability, transport essential nutrients into the cell, and function at the molecular and structural level. By atomic structure determination of a transporter of essential phosphate, and others of essential glucose, and of uric acid these transporters provide a roadmap to targeting these processes with inhibitors and activators, that will be of therapeutic advantage in cancers, and are of use in regulating the 'master' regulators in the cell.