Structural bases of the functional nucleic acids as the therapeutic target
| Project/Area Number |
10470476
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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 | University of Shizuoka |
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Principal Investigator |
FUJII Satoshi School of Pharmaceutical Sciences, University of Shizuoka, Professor, 薬学部, 教授 (10107104)
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| Project Period (FY) |
1998 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥10,200,000 (Direct Cost: ¥10,200,000)
Fiscal Year 2000: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1999: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 1998: ¥4,100,000 (Direct Cost: ¥4,100,000)
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| Keywords | Protein-nucleic acids complex / Structural based modeling / Structure-Activity relationship / alkylated base / repair mechanism / Molecular replace method / Protein Crystallography / Hydrolysis mechanism / 機能性核酸 / 蛋白質結晶解析 / ドラッグデザイン / リボザイム / インフルエンザ / 構造生物学 |
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| Research Abstract |
1) To obtain the good crystal of proteins and nucleic acids, several skillful techniques including the dynamic light scattering and crystal scoring have been introduced in house laboratory. 2) Single crystal structure of r(UGAGCUUCGGCUC) which adopts the successive non-canonical base pairings (two G-U's and two U-U's) has been determined by X-ray method and the notable RNA double stranded structure was elucidated from structural chemical analysis. The A' form is cleared by using kink parameters. 3) The kink parameters would provide the tolerant aspect for irregular helical structures of nucleic acid. The tentative database including these kink parameters has been constructed by referred to NDB (Nucleic Acid Database) project. Using NDB software package and mmCIF dictionary, the several related programs are developed. The user can display results list that was selected with several descriptors for the structure definition and sequence properties. There are several factors stabilizing or
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destabilizing the conformation of a protein. A useful approach for estimating the contribution of these factors is to systematically analyze the thermodynamic data obtained from calorimetry and combine this with X-ray analyses of the structures for a series of single mutant proteins. 4) Escherichia coli Alk-A is induced during adoption to alkylation and catalyzes the excision of a variety of alkylated bases. The three-dimensional structure of Alk-A can review the detailed mechanism to recognize DNA base specificity in addition to the reaction mechanism. The model structure of protein complexed with the double helical DNA is elucidated from X-ray structures of related DNA glycosylase enzymes and mutagenic studies. The free enzyme structure has no difficulty in building the platform to afford the bended and wedge DNA with the flipped out nucleotide. The helix-hairpin-helix motif and the insertion residue L125 in free structure can be located without severe contacts. The alkylated base is surrounded with a variety of aromatic rings, such as W218, W272, Y273 and F18. The aromatic indole ring of tryptophan is a good candidate for forming the stacking with the positively charged base moiety n-cation interaction). Some hydrophobic residues, such as V128 and L240, also attend to substrate 5) Same model for substrate recognition and hydrolysis mechanism of MutT, repair enzyme was elucidated from X-ray structure and computer graphical studies. Less
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Report
(4 results)
Research Products
(18 results)
