Agonist induced conformational changes in the NMDA receptor

摘要： NMDA 受体是配体门控离子通道，在中枢神经功能中发挥关键作用 系统并参与突触可塑性、学习和记忆等过程。除了他们的 除了生理功能外，NMDAR 还与许多神经系统疾病和病症有关， 包括缺血性中风和癫痫。 NMDA 受体发挥的不同作用使得至关重要 这些受体的功能和调节已被充分了解。最近的结构提供了对 NMDA 受体的结构和终态结构为结构动力学提供了丰富的基础 对受体的研究将允许对所有构象状态进行详细研究 蛋白质探索。这是必需的，因为仍有几个未解答的问题，例如机制 潜在的部分激动以及谷氨酸和谷氨酸之间的变构通讯机制 甘氨酸结合。单分子福斯特共振能量转移 (smFRET) 方法非常适合 此类研究可以表征蛋白质探测和动力学的所有状态 状态之间的转换，然后可以与可用的广泛功能信息相关联 对于受体。本文提出的研究旨在通过两个方面来填补这些重要的知识空白 目的：确定 NMDA 受体部分激动的机制并研究变构 NMDA 受体的谷氨酸和甘氨酸结合亚基之间的通讯。研究 拟议的建议将在理解该机构的职能和监管方面向前迈出重要一步 NMDA 受体。因此，这项研究工作符合 NIGMS 的既定使命，即支持 “基础研究可以增加对生物过程的理解，并为生物过程的进步奠定基础 疾病的诊断、治疗和预防”。

Abstract: NMDA receptors are ligand-gated ion channels that play a critical role in the function of the central nervous system and are involved in processes such as synaptic plasticity, learning, and memory. In addition to their physiological functions, NMDARs are also implicated in a number of neurological diseases and conditions, including ischemic stroke and epilepsy. The diverse roles that NMDA receptors fill make it critical that the function and regulation of these receptors are fully understood. The recent structures have provided insight into the architecture and end state structures of NMDA receptors providing a rich foundation for structure- dynamic investigation of the receptor which will allow for detailed investigations of all the conformational states that the protein explores. This is required as there are still several unanswered questions such as mechanism underlying partial agonism as well as mechanism of allosteric communication between the glutamate and glycine binding. Single molecule Förster Resonance Energy Transfer (smFRET) method is ideally suited for such investigations as it allows for the characterization of all the states that the proteins probes and dynamics of transitions between the states, which then can be correlated to the extensive functional information available for the receptor. The research proposed herein seeks to fill these important gaps in knowledge through two aims: to Determine the mechanism of partial agonism in the NMDA receptor and to Study the allosteric communication between the glutamate- and glycine-binding subunits of the NMDA receptor. The research proposed will provide a significant step forward in the understanding of the function and regulation of the NMDA receptor. This research pursuit, therefore, is in keeping with the stated mission of the NIGMS to support “basic research that increases understanding of biological processes and lays the foundation for advances in disease diagnosis, treatment and prevention”.