ANOMALOUS SIGNAL OF SOLVENT BROMIDES USED FOR PHASING OF LYSOZYME

用于溶菌酶定相的溶剂溴化物的异常信号

• 批准号: 6205781
• 负责人: ZBIGNIEW DAUTER
• 金额: --
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6205781
• 关键词: biological products; biomedical resource; growth /development; infection; proteins; spectrometry

GPRTase catalyzes the pyrophosphorolysis of 5-purine nucleotides. Mutations in GPRTase are associated with Lesch-Hyhan disease, a major clinical neurodegenerative disorder. Parasitic organsims such as malaria and schistosomes cannot perform de novo purine biosynthesis and thus depend on the ability to salvage purines from host nucleotides. Thus HGPRTase is an excellent therapeutic target, provided that sufficient discrimination can be achieved between the human and parasitic enzymes. This is especially important in the case of malaria, as strains resistant to the existing antibiotics are becoming prevalent world wide. We have recently collected data on the complex between human HGPRTase bound to inorganic pyrophosphate and the transition state inhibitor to 2.2E on X-9B. The refined structure clearly identified the binding mode of the transition state analog, bound magnesium ion and pyrophosphate, as well as the interacting protein ligands. This structure also identifies the interactions responsible for stabilization of the oxycarbonium intermediate. We have very recently collected data to 2.0E of the malarial enzyme bound to the same set of inhibitory ligands. This represents the first report of the malarial enzyme crystallizing and will provide the opportunity to design malaria specific inhibitors.

GPRTase催化5-羟基-1，2-二氢-1，3-二氧戊环的焦磷酸解- 嘌呤核苷酸。 GPRTase的突变与Lesch-Hyhan病有关，这是一种主要的 临床神经退行性疾病 寄生生物，如 疟疾和寄生虫不能进行嘌呤的从头生物合成 因此依赖于从宿主体内回收嘌呤的能力 个核苷酸 因此，HGPRT酶是一个极好的治疗靶点， 只要能够在以下两种情况之间实现充分的区分， 人类和寄生虫酶。 这一点在本案中尤为重要 疟疾，因为对现有抗生素有抗药性的菌株 在世界范围内流行。 我们最近收集了有关 与无机焦磷酸结合的人HGPRT酶和 X-9 B上2.2E的过渡态抑制剂。 精致的结构 清楚地确定了过渡态类似物的结合模式， 结合镁离子和焦磷酸盐，以及相互作用 蛋白质配体。 该结构还标识了 负责氧碳中间体的稳定化。 我们 我最近收集了2.0E疟疾酶结合的数据， 同一组抑制配体。 这是第一个 报告的疟疾酶结晶，并将提供 设计疟疾特异性抑制剂的机会。