CONFORMATIONAL CHANGES OF ENZYME GLUTAMATE RACEMASE BY SAXS & WAXS

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。 炭疽杆菌已被美国疾病控制和预防中心列为高度优先的A类制剂，因为它在发生生物恐怖袭击时可能造成大量人员伤亡。微生物获得抗生素耐药性的能力，以及选择具有多重耐药性的炭疽菌株的可行性，创造了对针对这些致命细菌的新型抗菌药物的需求。谷氨酸消旋酶(RACE)负责将L-谷氨酸转化为D-谷氨酸，D-谷氨酸是肽聚糖生物合成的重要组成部分。RACE酶是细菌生长所必需的，而且它们缺乏人类同源物，这使它们成为设计和开发抗菌治疗药物的有吸引力的靶标。炭疽菌基因组中存在两种可能的谷氨酸消旋酶同工酶，分别为racE1和racE2。研究表明，在溶液中，在没有底物的情况下，race1是单体，但在底物存在的情况下，会发生二聚反应。RacE2是一种二聚体，与底物的存在无关。这些酶与底物结合的晶体结构表明，它们应该具有开放和封闭的构象，因此在溶液中应该经历显著的构象变化。溶液分散实验将帮助我们回答以下问题-(1)这些酶在催化过程中经历了什么构象变化(2)race1的二聚化过程是如何与催化联系起来的。这些信息将帮助我们更好地了解这些酶在溶液中的构象，这将指导我们完成基于结构的药物设计过程。

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. Bacillus anthracis has been classified by the Centers for Disease Control and Prevention as a high-priority, category A agent, based upon its potential for causing mass casualties in the event of a bioterrorist attack. The ability of microbes to acquire antibiotic resistance, as well as the feasibility of selecting multi-drug resistant strains of anthrax, has created a need for novel antimicrobial drugs that target these lethal bacteria. Glutamate racemase (RacE) is responsible for converting L-glutamate to D-glutamate, which is an essential component of peptidoglycan biosynthesis. RacE enzymes are essential for bacterial growth, and they lack a human homolog making them attractive targets for the design and development of antibacterial therapeutics. There are two putative glutamate racemase isozymes, RacE1 and RacE2, in the B. anthracis genome. Studies indicate that RacE1, in solution, is a monomer in the absence of substrate but dimerizes when substrate is present. RacE2 is a dimer irrespective of the presence of substrate. The crystal structures of these enzymes bound to substrate indicate that they should have an open and a closed conformation and should therefore undergo significant conformational changes in solution. Solution scattering experiments will help us answer the following questions- (1) what are the conformational changes that these enzymes undergo during catalysis (2) how is the process of dimerization for RacE1 connected with catalysis. This information will help us obtain a better understanding of the conformations of these enzymes in solution which will guide us through the structure based drug design process.