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的一个 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。 酪氨酸磷酸酶PTP-1B是胰岛素信号传导和葡萄糖稳态的调节剂，该酶的抑制剂将是用于治疗糖尿病及其并发症的有用的新疗法。 在这里，我们提出了基于结构的PTP-1B抑制剂的设计，使用分离拴系靶向活性位点和最近发现的新的变构位点。 我们需要使用同步加速器来生成支持活性和变构位点抑制剂的药物设计所需的高质量衍射数据，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.