STRUCTURAL PARAMETERS INVOLVED IN METAL RECOGNITION

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。 生物控制过渡金属离子的机制以及这些金属在细胞调控中的作用已成为矿物生物化学中的关键研究领域。生物系统需要特定的金属结合和反应，以避免金属之间在蛋白质表达、特定金属的吸收以及将正确的金属掺入酶活性部位的串扰。金属蛋白如何识别、结合和响应所需金属离子的存在的细节还没有很好地确定。过渡金属离子尤其如此，其中许多离子具有相似的电荷和离子半径。因此，配位几何构型和配体偏好在区分过渡金属方面可能起着重要的作用。这一研究项目的总体目标是了解参与金属运输的金属蛋白中构成特定金属结合的结构参数，以及相关蛋白质对特定金属结合的结构反应。为此，我们计划使用XAS来检测镍转运蛋白中镍位点的结构，包括：金属调节蛋白(NikR)、金属转运蛋白(NikABCDE)和金属配位转运蛋白(HYPA)--这些蛋白都与大肠杆菌中的镍运输有关，以及它们在幽门螺杆菌中的同源物。细菌的生存能力，包括人类病原体(如幽门螺杆菌)，与所需金属(包括镍)的获取有关，已证明几种人类疾病是由金属贩运的崩溃引起的(例如，铜的威尔逊病和门克斯病、遗传性血色沉着病和其他遗传性铁超载疾病)。此外，对金属运输中涉及的结构参数的详细了解可能会导致新的抗生素干扰细菌的金属代谢，这通常是致病过程中必不可少的，并培育出对金属具有抗性并有助于生物修复的植物。

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 mechanisms by which organisms control transition metal ions and the roles of these metals in cellular regulation have emerged as key areas of investigation in metallobiochemistry. Specific metal binding and responses are required by biological systems in order to avoid cross-talk between metals in the expression of proteins, in the uptake of specific metals, and for the incorporation of the correct metal into enzyme active sites. The details of how the metalloproteins recognize, bind and respond to the presence of the requisite metal ion are not well established. This is particularly true for transition metal ions, many of which have similar charges and ionic radii. Thus, it seems likely that coordination geometry and ligand preferences play important roles in distinguishing transition metals. The overall objective of this research project is to understand the structural parameters that underlie metal-specific binding, and the related protein structural responses to specific metal binding, in metalloproteins involved in metal trafficking. Toward this goal, we plan to use XAS to examine the structures of Ni sites in nickel trafficking proteins including: a metalloregulator (NikR), a metallotransporter (NikABCDE) and a metallochaperone (HypA)--proteins all involved in nickel trafficking in E. coli, and their homologs in H. pylori. The viability of bacteria, including human pathogens (like H. pylori), is linked to the acquisition of required metals (including Ni), and several human diseases have been shown to result from a breakdown in metal trafficking (e.g., Wilson's and Menkes¿ diseases for copper, genetic hemochromatosis and other hereditary iron overload disorders for iron). In addition, a detailed understanding of the structural parameters involved in metal-trafficking may lead to new antibiotics that interfere with bacterial metal metabolism, which is frequently essential for pathogenesis, and the development of plants that are resistant to metals and useful in bioremediation.