BREAKAWAY TETHERING AND STRUCTURE-BASED DESIGN OF NOVEL PTP 1B INHIBITORS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 酪氨酸磷酸酶PTP-1B是胰岛素信号和血糖稳态的调节者，该酶的抑制剂有望成为治疗糖尿病及其并发症的新药物。在这里，我们提出了基于结构的PTP-1B抑制剂的设计，使用分离拴系来靶向活性部位和最近发现的一个新的变构部位。我们需要访问同步加速器来生成高质量的衍射数据，以支持活性和变构位置的抑制剂的药物设计，因为我们只能在内部实现中到低分辨率的数据集。此外，使用同步加速器将有助于实现到目前为止难以实现的目标，即全长PTP-1B的晶体结构。

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 tyrosine phosphatase PTP-1B is a regulator of insulin signaling and glucose homeostasis and inhibitors of this enzyme would be useful new therapeutics for the treatment of diabetes and its complications. Here we propose structure-based design of PTP-1B inhibitors using breakaway tethering to target both the active site and a recently discovered novel allosteric site. We need access to the synchrotron to generate the high quality diffraction data required to support drug design of inhibitors of the active and allosteric sites since we have only been able to achieve medium to low resolution data sets in-house. In addition, use of the synchrotron would facilitate what has been up to now an elusive objective, a crystal structure of the full-length PTP-1B.