Expansion of structure biology studies on human defense and response proteins for drug design based on three-dimensional-structures

扩展人类防御和反应蛋白的结构生物学研究，用于基于三维结构的药物设计

基本信息

批准号：
14370727
负责人：
SATOW Yoshinori
金额：
$ 8.77万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

For drug design based on three-dimensional structures of defense and response proteins such as human receptors and disease-related enzymes, structural biology studies utilizing X-ray crystallography are carried out on these proteins. The studies have further expanded the methods for structure study and their application.Bacterial Lipopolysaccharide is recognized by human MD-2 proteins that associated with human Toll-Like receptor 4 (TLR4). The TLR4 complex with MD-2 transmits bacterial infection signals to cell cytosol, triggers defense response to the infection, and causes endotoxin shocks known as septicemia. Human and mouse MD-2 proteins are expressed in yeast and then highly purified. Crystals are obtained for human MD-2. Attempts to express human TLR4 are also carried out. Human heat-shock protein HSP40 and β2 trans-membrane receptor are also expressed, purified, and subjected to crystallization attempts.Human β-galactosidasese and α-N-acetylgalactosaminidase are lysosomal enzymes … More hydrolyzes galactoside linkages in various glycolipids, and its genetic mutations decrease enzymatic activities which result in deficiencies of glycolipid metabolism and hence accumulate substrates in organs, causing lysosomal diseases. These enzymes are expressed and subjected to crystallographic studies. The structure of human tissue factor protein in complex with humanized antibody Fab is determined for drug design of blood-coagulation inhibitorsYeast homing endonuclease derived from VMA1 gene is structurally studied for full elucidation of its binding to double-stranded substrate DNAs. To elucidate its precise reaction mechanisms of protein splicing in this endonuclease, a series of crystal structural studies has been carried out with the use of splicing-inactive and slowly spliceable precursors. Pathogenic protein SEp22 from Salmonella enteritidis is expressed, purified, and crystallized. The structure of SEp22 determined for two crystal forms has revealed 12-subunitit oligomer in 23 symmetry and iron ion binding for protection of its DNA. Cassette recombinases of Staphylococcus aureus (SA) are expressed and purified for understanding of methicillin-resistant SA diseases. Less

对于基于防御和反应蛋白的三维结构（例如人体受体和疾病相关酶的生物学研究）的药物设计，使用X射线晶体图的生物学研究是在蛋白质上进行的。 2与人Toll样受体4相关的蛋白质（TLR4）与MD-2的复合物传递给细胞溶胶，触发对感染的防御反应，并引起内毒素冲击。 Shock Protein HSP40 and β2 Trans -Membrane Receptor Are Also Expressed, and Subjected to Crystallization Attempts.human β-GalactoseSASESESESESESAM Inidase Are Lysosomal Enzymes ... More Hydroryzzide Linkages in Various Glycolipids Ties Which Result in Deficiencies of Glycolipid Metabolism and Henstrate SubstrateS in Organs,这些酶进行了晶体学研究。为了在此内核酸酶中阐明其剪接的原理，一系列的晶体研究是用什一堂什一堂的tith tith tithe tithe tith tith the the the the the tith tith the the the the the the the the the the the the the the the the the the the the the the the the the在23个对称性中揭示了12个亚基的寡聚，并且对其DNA的保护（SA）进行了纯化和净化。