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/红藻氨酸和NMDA受体在药物寻找中发挥机制作用 成瘾是一种谷氨酸依赖性生理反应。 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有关的综合征。虽然 已经证明，AMPA、红藻氨酸和NMDA受体存在多种亚型， 由于高度同源性，难以开发亚型特异性拮抗剂 而不是它们的配体结合口袋。相比之下，谷氨酸受体亚型可以 与不同的细胞内信号级联通过突触相关 蛋白质（SAP）。SAP（例如，SAP 90和SAP 97）由五个独立的 结构域：三个PDZ结构域（PDZ 1、PDZ 2、PDZ 3），src-同源3结构域（SH 3）， 和鸟苷酰激酶样结构域（GK）。我们的研究表明，PDZ结构域 决定受体亚型的选择，而分子内相互作用 SAP不同结构域之间的相互作用调节受体功能。这里我们 我建议开发肽和肽模拟物， 特异性谷氨酸受体与SAP 90和SAP 97的相互作用， 下游信号蛋白。我们的目标是从结构上表征 SAP 90和SAP 97之间的相互作用。为了实现这一点， 高分辨率核磁共振和计算机模拟将被用来确定 PDZ 1和SH 3的结构特征，而与其他结构域的复合物， SAP 90和SAP 97以及来自NMDA、AMPA和红藻氨酸的片段 受体。高分辨率的结构将提供深入了解 受体、SAP和调节蛋白之间的相互作用， 负责受体的信号传导、聚集和再循环。 将实验确定的结构特征详细描述为 SAP 90和SAP 97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 更好地理解SAP 90和SAP 97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.