STRUCTURAL MODELING OF THE NMDA RECEPTOR CHANNEL

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 谷氨酸受体是脊椎动物中枢神经系统的主要兴奋性受体。NMDA受体是一类由N-甲基-D-天冬氨酸激活的谷氨酸受体，在学习和记忆中发挥重要作用。N-甲基-D-天冬氨酸受体离子通道对钠、钾和钙离子具有通透性。与NMDA受体相关的钙电流被认为在突触可塑性中发挥重要作用，包括诱导长时程增强和长时程抑制。NMDA受体具有强烈的电压依赖性，这是由于MG2的阻断所致。在静息电位下，NMDA电流被高度阻断，但膜去极化减轻了镁离子通道的阻断。人们对NMDA受体的结构和功能进行了大量的研究，但NMDA受体物理结构的关键成分仍不清楚。虽然已经有研究记录了沿着孔边和受体跨膜区其他部分的特定残基的可及性，但关于整体通道结构的原子水平信息很少，这对于理解镁离子的阻断和离子选择性很重要。为了研究通道结构，我们将建立NMDA受体通道的理论结构模型，并通过实验验证其有效性。NAK通道和NMDA受体一样，负责钠和钾的传导，具有中等程度的序列同源性，被认为具有与NMDA受体通道相似的结构。我的实验室研究生Beth Siegler Retchless建立了基于NAK通道的NMDA受体通道的初步同源模型，并成功地预测了NR1上的残基和NR2a上相互作用的残基。丹尼尔·史密斯(Daniel Smith)也是我实验室的一名研究生，他对西格勒·雷切斯的模型进行了扩展，将形成通道的更多蛋白质包括在内，并将使用同源建模和MD模拟等理论化学技术来开发更准确、更完整的NMDA受体通道结构模型。这个项目的主要目标是更好地了解NMDA受体通道的结构，以及它的结构如何解释它独特的生理特性。我们将研究给出通道形状的亚基-亚基相互作用，将使用我们的模型来预测相互作用的残基，并将实验测试我们的预测。

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. Glutamate receptors are the primary excitatory receptors in the CNS of vertebrates. NMDA receptors, a class of glutamate receptors that are activated by N-methyl-D-aspartate, play an important role in learning and memory. NMDA receptor ion channels are permeable to Na+, K+, and Ca2+. The Ca2+ currents associated with NMDA receptors are believed to play an important role in synaptic plasticity, including induction of long-term potentiation and long-term depression. NMDA receptors feature strong voltage dependence due to Mg2+ block. At resting potentials, NMDA currents are highly blocked, but membrane depolarization alleviates Mg2+ block. There has been much research into the structure and function of NMDA receptors, but key components of the physical structure of NMDA receptors remain unknown. While there have been studies documenting the accessibility of particular residues along the pore and on other portions of the receptor's transmembrane regions, there is little atomic level information on overall channel structure, which is important for understanding Mg2+ block and ion selectivity. In order to study channel structure, We will build a theoretical structural model of the NMDA receptor channel and experimentally test its validity. The NaK channel, which, like NMDA receptors, conducts Na+ and K+, has a moderate amount of sequence homology and is believed to have similar structure to the NMDA receptor channel. An initial homology model of the NMDA receptor channel based on the NaK channel was built by Beth Siegler Retchless, a graduate student in my lab, and successfully predicted a residue on NR1 and a residue on NR2A that interact with each other. Daniel Smith, also a graduate student in my lab, expanded Ms. Siegler Retchless's model to include more of the protein that forms the channel and will use theoretical chemistry techniques including homology modeling and MD simulations to develop a more accurate and complete model of the channel structure of NMDA receptors. The primary goal of this project is to develop a better understanding of the structure of the NMDA receptor channel and how its structure explains its unique physiological properties. We will study the subunit-subunit interactions that give the channel its shape, will use our model to predict interacting residues, and will experimentally test our predictions.