DEVELOPMENT OF TYPE II INHIBITORS FOR JNK3

这个子项目是许多利用 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。 JNK 3的抑制已被证明可以保护小鼠免受与帕金森病小鼠模型相关的多巴胺能神经元细胞损失。的疾病。迄今为止，I型ATP竞争性抑制剂已经被设计并成功结晶。然而，晶体结构处理的是无活性的蛋白质，并且对抑制剂结合到蛋白质的活性形式上的翻译的确切理解是未知的。MAP激酶家族中II型抑制剂的发现开辟了一种新的方法来特异性靶向非活性形式的酶，我们计划研究JNK 3。我们认为，这一途径将允许增加激酶和可能的JNK亚型特异性缺乏一个更传统的I型抑制剂。

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. The inhibition of JNK3 has been shown to protect mice from the dopaminergic neuronal cell loss associated in the mouse model of Parkinson?s disease. To date, Type I ATP competitive inhibitors have been designed and successfully crystallized. However, the crystal structures are dealing with inactive protein and the exact understanding of the translation of the inhibitor binding onto the active form of the protein is unknown. The discovery of Type II inhibitors in the MAP kinase family opened up a novel way to specifically target the inactive form of the enzyme which we plan on examining with respect to JNK3. We feel that this path will allow for the increase in kinase and possibly JNK isoform specificity lacking in a more traditional Type I inhibitor.