Drug Design: Glutamate Receptor Signaling

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通过 AMPA/海人藻酸受体和NMDA受体在药物寻找中都发挥着机制作用 上瘾是谷氨酸依赖性行为的一种形式。 AMPA/海人藻酸和NMDA受体拮抗剂具有临床应用潜力 与酒精和其他药物成瘾有关的综合症。虽然 已经证实，存在许多亚型的AMPA、海人藻酸和NMDA受体 由于同源性高，很难开发出亚型特异性拮抗剂 而不是他们的配体绑定口袋。相比之下，谷氨酸受体亚型可以 通过突触关联耦合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)， 和鸟氨酸激酶区(GK)。我们的研究表明，PDZ结构域 确定受体亚型的选择，同时分子内相互作用 在SAP的不同结构域之间调节受体功能。在这里我们 建议开发将扰乱分子的多肽和多肽仿生学 特异性谷氨酸受体与SAP90和SAP97的相互作用 下游信号蛋白。我们的目标是从结构上描述 SAP90和SAP97的域间相互作用。要做到这一点， 将利用高分辨率核磁共振和计算机模拟来确定 PDZ1和SH3的结构特征及其与其他结构域的复杂性 SAP90和SAP97以及NMDA、AMPA和Kainate的片段 感受器。这些高分辨率的结构将提供对 受体、SAP和调节蛋白之间的相互作用，它们是 负责受体的信号传递、聚集和循环。 将实验确定的结构特征融入到详细的 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。这种分子将允许一种 更好地了解SAP90和SAP97的功能，并提供 治疗药物成瘾的新途径。

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.