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曲目；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，由金属酶催化的反应在化学上具有挑战性，对生命至关重要，这并不奇怪。利用x射线晶体学和计算方法研究了复合金属辅助因子的结构和作用机理。我们的发现在仿生催化剂的合成和酶抑制剂的设计中具有应用价值。除了探讨金属酶的机制外，研究金属中心组装所需的微量矿物质水平的细胞调节以及研究组装过程本身也很重要。本文主要研究含镍和含铁硫的蛋白质及其金属伴侣，以及镍吸收和铁硫簇组装的调控。公共卫生相关性：拟议的研究使用x射线晶体学和计算作为主要工具来研究含镍、铁硫和类角质蛋白，重点关注参与单碳代谢的蛋白质。我们的目标是探索复杂金属辅助因子的机制和组装，以及镍吸收和铁硫簇生物发生的细胞调控。

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.