STRUCTURAL STUDIES OF MACROMOLECULAR SIGNALING COMPLEXES

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。 在过去的几年里，我们已经解决了哺乳动物表皮生长因子受体(SEGFR)胞外区的几个结构。基于我们和其他人的工作，我们提出了一个配体诱导该受体二聚化的模型，该模型对于理解该受体的正常激活以及如何抑制在许多癌症肿瘤中看到的异常激活具有重要意义。我们现在建议：(A)扩大我们对临床相关抗体使sEGFR失活的结构基础的研究；(B)继续我们对配体诱导sEGFR二聚化的结构基础的研究；(C)将相同的结构细节带到无脊椎动物的EGFR中，其中我们的生化数据表明昆虫受体的胞外区域的非活性构象和活性构象可能存在显著差异；(D)确定果蝇EGFR(DER)抑制剂Argos的结构，并了解其与DER配体相互作用的性质；(E)开始一系列新的大分子复合体在一些细胞内信号通路中的研究，包括新的磷脂酰肌醇结合蛋白和大的GTP酶。

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. Over the last few years we have solved several structures of the extracellular region of the mammalian epidermal growth factor receptor (sEGFR). Based on our, and others work, we have proposed a model for teh ligand induced dimerization of this receptor that has important implications in understanding both the normal activation of this receptor, and for how to inhibit the aberrant activation seen in numerous cancerous tumors. We now propose to (a) expand our study of the structural basis for inactivation of sEGFR by clinically relevant antibodies, (b) continue our studies of the structural basis of ligand-induced dimerization of sEGFR (c) bring the same structural detail to the invertebrate EGFRs, where our biochemical data suggest that there may be significant differences in both the inactive and active conformations o f the extracellular region of the insect receptors,(d) determine the structure of the Drosophilia EGFR (DER) inhibitor, Argos, and understand the nature of its interactions with DER ligands, (e) begin a series of new investigations of macromolecular complexes in a number of intracellular signaling pathways, including novel phosphoinositide binding proteins and large GTPases.