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）： 最近的研究提供了有力的证据，表明谷氨酸受体信号传导通过 AMPA/Kainate和NMDA受体都在寻求药物中起着机械作用 反应和成瘾是谷氨酸依赖性的一种形式。 AMPA/Kainate和NMDA受体拮抗剂具有临床的潜力 与对酒精和其他药物成瘾有关的综合征。虽然 存在AMPA，Kainate和NMDA受体的许多亚型，已证明 由于同源性很高，因此难以发展亚型特定拮抗剂 OT配体结合口袋。相反，谷氨酸受体亚型可以 通过突触相关 蛋白质（SAPS）。 SAPS（例如SAP9O和SAP97）由五个单独的 域：三个PDZ域（PDZ1，PDZ2，PDZ3），一个SRC-同源3域（SH3）， 和鸟苷激酶样结构域（GK）。我们的研究表明PDZ域 确定受体亚型的选择，而分子内相互作用 在SAP的不同域调节受体功能之间。我们在这里 提议开发肽和肽仪会破坏分子 特异性谷氨酸受体与SAP90和SAP97以及 下游信号蛋白。我们的目标是在结构上表征 SAP90和SAP97的域间相互作用。为此， 高分辨率NMR和计算机模拟将用于确定 PDZ1和SH3的结构特征，同时与其他领域复合 SAP90和SAP97以及NMDA，AMPA和Kainate的片段 受体。高分辨率结构将提供有关 受体，SAP和调节蛋白之间的相互作用， 负责受体的信号，聚类和回收利用。 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 对SAP90和SAP97的功能有更深入的了解，并提供 治疗吸毒的新途径。