Complex Metallocluster Structure and Assembly

描述（由申请人提供）：生物学中的金属离子允许扩展化学库;局部蛋白质环境和金属配位球协同作用，赋予独特的反应性。因此，毫不奇怪，金属酶催化的反应是化学上具有挑战性的，对生命至关重要。我们使用X射线晶体学和计算来研究复杂金属辅因子的结构和机制。我们的研究结果在仿生催化剂的合成和酶抑制剂的设计中具有应用。除了询问金属酶的机制，重要的是要调查微量矿物质水平的细胞调节所需的装配中心，以及研究装配过程本身。本研究的重点是镍和铁硫蛋白及其金属伴侣，以及镍吸收和铁硫簇组装的调控。公共卫生相关性：这项研究使用X射线晶体学和计算作为主要工具来研究含镍，铁硫和类corrinoid的蛋白质，重点是参与一碳代谢的蛋白质。我们的目标是探索复杂的金属辅因子的机制和组装，以及镍吸收和铁硫簇生物合成的细胞调节。

DESCRIPTION (provided by applicant): Metal ions in biology allow for an expanded chemical repertoire; the local protein environment and metal coordination sphere act synergistically to confer unique reactivity. It is therefore not surprising that the reactions catalyzed by metalloenzymes are chemically challenging and essential for life. We use X-ray crystallography and computation to study the structure and mechanism of complex metallocofactors. Our findings have applications for the synthesis of biomimetic catalysts and in the design of enzyme inhibitors. In addition to interrogating the mechanisms of metalloenzymes, it is important to investigate the cellular regulation of trace mineral levels required for metallocenter assembly, as well as to study the assembly process itself. This proposal focuses on nickel and iron-sulfur containing proteins and their metallochaperones, as well as the regulation of nickel uptake and iron-sulfur cluster assembly. PUBLIC HEALTH RELEVANCE: The proposed research uses X-ray crystallography and computation as the chief tools to investigate nickel, iron-sulfur and corrinoid containing proteins, with a focus on proteins involved in one-carbon metabolism. Our goals are to explore the mechanism and assembly of complex metallocofactors, as well as the cellular regulation of nickel uptake and iron-sulfur cluster biogenesis.