Drug Design: Glutamate Receptor Signaling

药物设计：谷氨酸受体信号传导

• 批准号: 6623499
• 负责人: DALE F MIERKE
• 金额: $ 14.78万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6623499
• 关键词: AMPA receptors; NMDA receptors; X ray crystallography; alcoholism /alcohol abuse; biological signal transduction; computer simulation; drug addiction; drug design /synthesis /production; glutamate receptor; green fluorescent proteins; immunoprecipitation; intermolecular interaction; molecular dynamics; nuclear magnetic resonance spectroscopy; physical model; protein binding; protein signal sequence; protein structure function; synapses; transcription factor

DESCRIPTION (provided by applicant): Recent studies provide strong evidence that glutamate receptor signaling, via both AMPA/kainate and NMDA receptors, play a mechanistic role in drug seeking responses and that addiction is a form of glutamate-dependent phisticity. AMPA/kainate and NMDA receptor antagonists have potential for clinical syndromes associated with addiction to alcohol and other drugs. Although numerous subtypes of AMPA, kainate, and NMDA receptors exist, it has proven difficult to develop subtype specific antagonists because of the high homology ot their ligand binding pockets. In contrast, glutamate receptor subtypes can couple to different intracellular signaling cascades via synaptic associated proteins (SAPs). SAPs (e.g., SAP9O and SAP97) are made up of five separate domains: three PDZ domains (PDZ1, PDZ2, PDZ3), a src-homology 3 domain (SH3), and a guanyl kinase-like domain (GK). Our studies show that the PDZ domains determine the selection of receptor subtype, while intra-molecular interactions between the different domains of SAPs regulate receptor function. Here we propose to develop peptides and peptidomimetics that will disrupt the molecular interactions of specific glutamate receptors with SAP90 and SAP97 and downstream signaling proteins. We aim to structurally characterize the inter-domain interactions of SAP90 and SAP97. To accomplish this, high-resolution NMR and computer simulations will be utilized to determine the structural features of PDZ1 and SH3 while complexed with the other domains of SAP90 and SAP97 as well as fragments from the NMDA, AMPA, and kainate receptors. The high-resolution structures will provide insight into the interactions between the receptors, SAPs, and regulatory proteins, which are responsible for the signaling, clustering and recycling of the receptors. Incorporating the experimentally determined structural features into detailed molecular models of SAP90 and SAP97 will allow for the rational design of molecular inhibitors of these interactions. Such molecules will allow for a greater understanding of the function of SAP90 and SAP97 as well as provide a novel route for the treatment of drug addiction.

描述（由申请人提供）： 最近的研究提供了强有力的证据表明谷氨酸受体信号传导通过 AMPA/红藻氨酸和 NMDA 受体在药物寻找中发挥机械作用 反应，成瘾是谷氨酸依赖性粘性的一种形式。 AMPA/红藻氨酸和 NMDA 受体拮抗剂具有临床应用潜力 与酒精和其他药物成瘾相关的综合症。虽然 已证明，存在多种 AMPA、红藻氨酸和 NMDA 受体亚型 由于同源性高，难以开发亚型特异性拮抗剂 ot 它们的配体结合口袋。相反，谷氨酸受体亚型可以 通过突触相关联到不同的细胞内信号级联 蛋白质（SAP）。 SAP（例如 SAP9O 和 SAP97）由五个独立的 结构域：三个 PDZ 结构域（PDZ1、PDZ2、PDZ3）、一个 src-同源 3 结构域（SH3）、 和鸟苷激酶样结构域 (GK)。我们的研究表明 PDZ 域 决定受体亚型的选择，同时分子内相互作用 SAP 的不同结构域之间调节受体功能。在这里我们 提议开发肽和肽模拟物来破坏分子 特定谷氨酸受体与 SAP90 和 SAP97 的相互作用以及 下游信号蛋白。我们的目标是从结构上表征 SAP90 和 SAP97 的域间交互。为了实现这一目标， 将利用高分辨率核磁共振和计算机模拟来确定 PDZ1 和 SH3 的结构特征，同时与其他结构域复合 SAP90 和 SAP97 以及来自 NMDA、AMPA 和红藻氨酸的片段 受体。高分辨率结构将提供对 受体、SAP 和调节蛋白之间的相互作用， 负责受体的信号传导、聚集和回收。 将实验确定的结构特征纳入详细的 SAP90 和 SAP97 的分子模型将允许合理设计 这些相互作用的分子抑制剂。这样的分子将允许 更好地了解 SAP90 和 SAP97 的功能并提供 治疗毒瘾的新途径。