| Project/Area Number |
14370727
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Physical pharmacy
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| Research Institution | The University of Tokyo |
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Principal Investigator |
SATOW Yoshinori The University of Tokyo, Graduate School of Pharmaceutical Sciences, Professor, 大学院・薬学系研究科, 教授 (30150014)
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| Co-Investigator(Kenkyū-buntansha) |
NOGUCHI Shuji The University of Tokyo, Graduate School of Pharmaceutical Sciences, Research Associate, 大学院・薬学系研究科, 助手 (60237823)
MIZUTANI Ryuta The University of Tokyo, Graduate School of Pharmaceutical Sciences, Research Associate, 大学院・薬学系研究科, 助手 (70272482)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥13,700,000 (Direct Cost: ¥13,700,000)
Fiscal Year 2004: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2003: ¥4,600,000 (Direct Cost: ¥4,600,000)
Fiscal Year 2002: ¥5,300,000 (Direct Cost: ¥5,300,000)
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| Keywords | Structure biology / X-ray Crystallography / Lysosome diseases / Blood coagulation factor / Salmonella enteritidis / Staphylococcus aureus / Innate immunology / Toll-like receptors / 抗体 / 受容体 / 三次元構造 |
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| Research Abstract |
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 inhibitors
Yeast 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
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