STRUCTURAL MODELING OF THE NMDA RECEPTOR CHANNEL

NMDA 受体通道的结构建模

• 批准号: 8171850
• 负责人: JOAN JOHNSON
• 金额: $ 0.11万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171850
• 关键词: Chemistry; Computer Retrieval of Information on Scientific Projects Database; Dependence; Funding; Glutamate Receptor; Goals; Grant; Homology Modeling; Institution; Ion Channel; Ions; Learning; Long-Term Depression; Long-Term Potentiation; Membrane; Membrane Potentials; Memory; Modeling; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR1 gene; Physiological; Play; Property; Proteins; Research; Research Personnel; Resources; Role; Sequence Homology; Shapes; Source; Structural Models; Structure; Synaptic plasticity; Techniques; Testing; Transmembrane Domain; United States National Institutes of Health; Vertebrates; base; graduate student; receptor; simulation; voltage

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.

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。 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受体是由N-甲基-D-天冬氨酸激活的一类谷氨酸受体，在学习和记忆中起重要作用。NMDA受体离子通道对Na+、K+和Ca 2+是可渗透的。与NMDA受体相关的Ca 2+电流被认为在突触可塑性中起重要作用，包括诱导长时程增强和长时程抑制。NMDA受体由于Mg 2+阻断而具有强的电压依赖性。在静息电位下，NMDA电流被高度阻断，但膜去极化加剧了Mg 2+阻断。对NMDA受体的结构和功能已经进行了大量的研究，但是NMDA受体的物理结构的关键组分仍然未知。虽然已经有研究记录了特定残基沿着孔和受体跨膜区的其他部分的可及性，但关于总体通道结构的原子水平信息很少，这对于理解Mg 2+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。与NMDA受体一样，NaK通道传导Na+和K+，具有中等程度的序列同源性，并被认为具有与NMDA受体通道相似的结构。我实验室的研究生Beth Siegler Retchless建立了基于NaK通道的NMDA受体通道的初始同源模型，并成功预测了NR 1上的一个残基和NR 2A上的一个残基相互作用。丹尼尔史密斯，也是我实验室的一名研究生，扩展了Siegler Retchless女士的模型，包括更多形成通道的蛋白质，并将使用理论化学技术，包括同源建模和MD模拟，以开发一个更准确和完整的NMDA受体通道结构模型。该项目的主要目标是更好地了解NMDA受体通道的结构及其结构如何解释其独特的生理特性。我们将研究亚基-亚基相互作用，使通道的形状，将使用我们的模型来预测相互作用的残留物，并将实验测试我们的预测。