Agonist induced conformational changes in the NMDA receptor

摘要： NMDA受体是一种配体门控的离子通道，在中枢神经系统的功能中起着关键作用 神经系统，并参与突触可塑性，学习和记忆等过程。除了它们 除了生理功能外，NMDAR还涉及许多神经疾病和病症， 包括缺血性中风和癫痫NMDA受体所起的不同作用使其在治疗中发挥重要作用。 这些受体的功能和调节是完全清楚的。最近的结构提供了深入了解 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 研究受体，这将允许详细研究所有的构象状态， 蛋白质探索这是必要的，因为仍然有几个未回答的问题，如机制 潜在的部分激动作用以及谷氨酸和 甘氨酸结合单分子Förster共振能量转移（smFRET）方法非常适合于 这样的调查，因为它允许表征的所有国家的蛋白质探针和动力学 状态之间的转换，然后可以将其与可用的广泛功能信息相关联 for the receptor受体.本文提出的研究旨在通过两个方面填补这些重要的知识空白 目的：探讨NMDA受体部分激动的机制，研究NMDA受体的变构作用， 在NMDA受体的谷氨酸和甘氨酸结合亚基之间的通信。研究 建议将提供一个重要的一步，在理解的功能和监管的 NMDA受体。因此，这项研究工作符合国家地理研究所的既定使命， “基础研究增加了对生物过程的理解，并为以下方面的进步奠定了基础： 疾病诊断、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”.