2004 Fiscal Year Final Research Report Summary
Structural Basis for mechanisms of preventing genomic instability
| Project/Area Number |
15390016
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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 | KUMAMOTO UNIVERSITY |
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Principal Investigator |
YAMAGATA Yuriko KUMAMOTO UNIVERSITY, FACULTY OF MEDICAL AND PHARMACEUTICAL SCIENCES, PROFESSOR, 大学院・医学薬学研究部, 教授 (40183678)
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| Project Period (FY) |
2003 – 2004
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| Keywords | Preventing genomic instability / Enzyme-substrate interaction / Protein Crystallography / Structural biology / Bio-molecular interaction |
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| Research Abstract |
Cellular DNAs, RNAs and Nucleotides are remarkable instable. Therefore cells have varieties of preventing systems for genomic instability. In this study, we target the proteins which work during pre-, first or middle stage of DNA replication. Our research purpose is to elucidate the preventing mechanisms for the genomic instability at the atomic level by the determinations of these protein structures.
The structures of MutT and hMTH1 were determined in the complexes with substrates and products by X-ray crystallography. The crystal structures of MutT alone, and in complex with a product, 8-oxo-dGMP(MutT-8-oxo-dGMP) have shown that MutT specifically recognizes 8-oxo-dGMP through a wealth of hydrogen bonds to the protein and waters in the binding pocket with the large ligand-induced conformational change. The mammalian counterpart of MutT, MutT homolog-1(MTH1), can hydrolyze a variety of nucleoside triphosphates containing oxidized adenine. The structural basis for the difference of the substrate specificity between MutT and hMTH1 is of fundamental interest. The crystal structure of MTH1 complexed with a product, 8-oxo-dGMP(hMTH1-8-oxo-dGMP) shows that the means of 8-oxoG recognition by hMTH1 are different from those found in the structure of MutT-8-oxo-dGMP. The structure of the substrate-binding pocket in hMTH1-8-oxo-dGMP suggests that hMTH1 can recognize several oxidatively damaged purine nucleoside triphosphates without a large conformational change.
The crystals of N-terminally His-tagged NUDT5 grew, but the resolution of the diffraction was relatively low. Now we are trying to get the crystals diffracting to a higher resolution by cutting the His-Tag.
The crystallization trials of purified primase and AlkB were in progress.
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[Journal Article] Optimal site-specific PEGylation of mutant TNF-α improves its antitumor potency2004
Author(s)
Y.Yoshioka, Y.Tsutsumi, S.Ikemizu, Y.Yamamoto, H.Shibata, T.Nishibata, Y.Mukai, M.Okamoto, M.Taniai, T.Shimizu, M.Kawamura, Y.Abe, S.Nakagawa, S.Nagata, Y.Yamagata, T.Mayumi
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Journal Title
Biochem Biophys Res Commun. 315
Pages: 808-814
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The Crystal Structure of the Tryptophan Synthase β Subunit from the Hyperthermophile, Pyrococcus furiosus : Investigation of Stabilization Factors.2004
Author(s)
Hioki, Y., Ogasahara, K., Lee, S., Ma, J., Ishida, M., Yamagata, Y., Matsuura, Y., Ota, M., Ikeguchi, M., Kuramitsu, S., Yutani, K.
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Journal Title
Eur.J.Biochem. 271
Pages: 2624-2635
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Structure of human MTH1, a Nudix family hydrolase that selectively degrades oxidized purine nucleoside triphosphates.2004
Author(s)
Mishima, M., Sakai, Y., Itoh, N., Kamiya, H., Furuichi, M., Takahashi, M., Yamagata, Y., Iwai, S., Nakabeppu, Y., Shirakawa, M.
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Journal Title
J.Biol.Chem. 279
Pages: 33806-33815
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Functionalization of TNF-α using phage display technique and PEGylation improves its antitumor therapeutic window.2004
Author(s)
Sibata, H., Yoshioka, Y., Ikemizu, S., Kobayashi, K., Yamamoto, Y., Mukai, Y., Okamoto, T., Taniai, M., Kawamura, M., Abe, Y., Nakagawa, S., Nagata, S., Yamagata, Y., Mayumi, T., Tsutsumi, Y.
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Journal Title
Clinical Cancer Res. 10
Pages: 8293-8300
Description
「研究成果報告書概要(欧文)」より
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