STRUCTURAL STUDIES ON NEURORECEPTORS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本课题组的研究旨在了解神经传递中的膜受体、酶和离子通道的生物活性和物理性质的分子基础。为了实现我们的目标，三维结构主要通过X射线晶体学确定，靶蛋白的功能特性通过基于结构的定点诱变结合生物物理和生物化学技术（包括电生理学）进行评估。具体来说，我们将重点放在三个类别的膜整合蛋白，它们在介导神经元活动中发挥关键作用：NMDA受体，一种配体门控阳离子通道，在与谷氨酸和甘氨酸结合时打开并介导兴奋性突触传递; LDL受体相关蛋白（LRP），一种与NMDA受体相关并调节突触传递强度的脂蛋白受体;和γ-分泌酶，一种膜内裂解蛋白酶（iCLIP），其介导淀粉样前体蛋白（APP）的调节性膜内蛋白水解（RIP）以调节淀粉样β（阿尔茨海默病的致病产物）的产生。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The research in my group is aimed at understanding molecular basis for biological activity and physical properties of integral membrane receptors, enzymes and ion channels involved in neurotransmission. To achieve our goals, three-dimensional structures are determined primarily by x-ray crystallography and functional properties of target proteins are assessed by structure-based site-directed mutagenesis in combination with biophysical and biochemical techniques including electrophysiology. Specifically, we are focusing on three classes of integral membrane proteins, which play key roles in mediating neuronal activities: NMDA receptors, a ligand-gated cation channel that opens upon binding to glutamate and glycine and mediate excitatory synaptic transmission; LDL receptor related protein (LRP), a lipoprotein receptor that associate with NMDA receptors and regulate the strength of synaptic transmission; and gamma-secretase, an intramembrane cleaving protease (iCLIPs) that mediate regulated intramembrane proteolysis (RIP) of amyloid precursor protein (APP) to regulate the production of amyloid beta, a pathogenic product for Alzheimer's disease.