CRYSTALLOGRAPHIC STUDIES OF DIHYDROFOLATE REDUCTASES

二氢叶酸还原酶的晶体学研究

• 批准号: 3164674
• 负责人: JOSEPH KRAUT
• 金额: $ 12.66万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-05-01 至 1991-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3164674
• 关键词: Escherichia coli; NAD(H) phosphate; X ray crystallography; antibiotics; antineoplastics; bacterial proteins; chemical structure function; chickens; cofactor; dihydrofolate reductase; drug design /synthesis /production; enzyme inhibitors; enzyme mechanism; enzyme structure; enzyme substrate complex; gonorrhea; isozymes; methotrexate; protein sequence

The guiding objective of the proposed research is to increase our understanding of the mechanism of action of dihydrofolate reductase (DHFR) in terms of its molecular structure. DHFR is the target of antifolate drugs such as methotrexate, trimethoprim and pyrimethamine, which are useful as antineoplastics and antibiotics. Detailed understanding of the structure of this molecule and how it functions should aid in efforts to design more sophisticated disease-specific inhibitors. Specific aims include determining the structure of folate (substrate) containing complexes of the enzyme from E. coli and chicken; refinement at high resolution of the R-67-plasmid DHFR; elucidation of the chicken enzyme structure when it is activated by mercurials; and to crystallize the R-plasmid enzyme in a complex with substrate and cofactor.

拟议研究的指导目标是增加我们的 了解二氢叶酸还原酶（DHFR）作用机理 就其分子结构而言。 DHFR是抗叶酸的靶标 甲氨蝶呤，甲氧苄啶和乙胺胺等药物， 用作抗肿瘤和抗生素。 对 该分子的结构及其运作方式应有助于努力 设计更复杂的疾病特异性抑制剂。 具体目的包括确定叶酸的结构（底物） 含有大肠杆菌和鸡的酶的复合物；精致 R-67质量DHFR的高分辨率；阐明鸡肉酶 结构被汞激活时；并结晶 与底物和辅因子的复合物中的R质粒酶。