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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。酪氨酸磷酸酶PTP-1B是胰岛素信号和葡萄糖稳态的调节因子，该酶的抑制剂将成为治疗糖尿病及其并发症的有效新疗法。在这里，我们提出了基于结构的PTP-1B抑制剂设计，使用分离系缚来靶向活性位点和最近发现的新变构位点。我们需要使用同步加速器来生成高质量的衍射数据，以支持活性和变弹性位点抑制剂的药物设计，因为我们只能在内部获得中低分辨率的数据集。此外，同步加速器的使用将有助于实现迄今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.