STRUCTURAL STUDIES OF MACROMOLECULAR SIGNALING COMPLEXES

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， 因此可以在其他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。 在过去的几年中，我们已经解决了哺乳动物表皮生长因子受体（sEGFR）的细胞外区域的几个结构。 基于我们和其他人的工作，我们已经提出了一个模型的配体诱导的二聚体的这种受体，有重要的意义，在理解这两种受体的正常激活，以及如何抑制异常激活在许多癌性肿瘤。 我们现在建议（a）扩展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的sEGFR二聚化的结构基础的研究，（c）将相同的结构细节引入无脊椎动物EGFR，其中我们的生物化学数据表明，昆虫胞外区的非活性和活性构象可能存在显着差异，受体，（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）开始对许多细胞内信号传导途径中的大分子复合物进行一系列新的研究，包括新的磷酸肌醇结合蛋白和大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.