Wet-Dry融合アプローチを用いた産業応用酵素の遷移状態制御による新機能創製
Project/Area Number |
17KT0010
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Multi-year Fund |
Section | 特設分野 |
Research Field |
Transition State Control
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Research Institution | Rikkyo University |
Principal Investigator |
常盤 広明 立教大学, 理学部, 教授 (10221433)
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Co-Investigator(Kenkyū-buntansha) |
中野 祥吾 静岡県立大学, 食品栄養科学部, 助教 (80748541)
石川 岳志 鹿児島大学, 理工学域工学系, 教授 (80505909)
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Project Period (FY) |
2017-07-18 – 2020-03-31
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Project Status |
Discontinued (Fiscal Year 2019)
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Budget Amount *help |
¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000)
Fiscal Year 2019: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2018: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2017: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
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Keywords | 産業応用酵素 / 人工酵素 / 第一原理計算 / 分子動力学シミュレーション / 高解像度X線構造解析 / フラグメント分子軌道計算 / 基質特異性 / PyMOL plug-inアプリケーション / Wet-Dry融合 / フラグメント分子軌道法 / 高分解能構造 / 遷移状態制御 / X線結晶構造解析 |
Outline of Annual Research Achievements |
高い選択能を有する酵素の特性を生かした産業応用酵素群の開発は、資源の乏しい我が国において世界を牽引する科学技術革新として極めて重要な課題である。 そこで本研究では、高精度な第一原理計算を用いた『Dry (計算化学、バイオインフォマティクス) 』手法と熱化学測定やX線結晶構造解析などを用いた『wet(酵素化学、構造生物学)』実験とを融合した新たなアプローチにより、高い選択能を有する酵素の特性を生かした産業応用酵素群を合理的に設計・開発することを目的としている。実際の対象としては、血液サンプル中に含まれる特定のアミノ酸、L-Thr濃度の定量計測への応用が期待されている短鎖型L-スレオニン脱水素酵素(TDH)等の標的タンパク質を取り上げた。特に、酵素反応における遷移状態を明らかにするだけでなく、天然型酵素の機能を目的に合わせて改変し、反応そのものを分子レベルで制御することで、天然酵素の活性を凌駕し、適用範囲を拡大した人工タンパク質(人工酵素)の合理的設計開発を目指した。最終的には、各種標的酵素だけに留まらず、創薬標的の中心である核内受容体やウイルスタンパク質に対する理論的解析についても推進した。特に、FMO計算に基づいて、標的タンパク質と基質・リガンドとの各種相互作用エネルギーを効率的に3D表示をする汎用化ツール群の開発に成功した。これらの結果は国内外の学会等で発表するとともに、専門誌(J.Chem.Info.Model)に公表した。このツール群の詳細な解説および酵素系への応用については、Springerより今年度発刊予定の書籍中に掲載することとなった。さらに、これまでの構造を基盤とした解析に加えて、配列解析に基づくバイオインフォマティックスを利用した新たなWet-Dry融合解析により、実際に応用可能なレベルに機能向上した標的タンパク質の合理的な創製への道を開くことができた。
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Report
(3 results)
Research Products
(108 results)
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[Journal Article] Development of analysis toolkit to visualize interaction energies generated by fragment molecular orbital calculations2018
Author(s)
Takaki Tokiwa, Shogo Nakano, Yuta Yamamoto, Takeshi Ishikawa, Sohei Ito, Vladimir Sladek, Kaori Fukuzawa, Yuji Mochizuki, Hiroaki Tokiwa, Fuminori Misaizu, and Yasuteru Shigeta
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Journal Title
J. Chem. Info. Model
Volume: 59(1)
Issue: 1
Pages: 25-30
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Dual conformation of the ligand induces the partial agonistic activity of retinoid X receptor α (RXRα)2018
Author(s)
Yurina Miyashita, Nobutaka Numoto, Sundaram Arulmozhiraja, Shogo Nakano, Naoya Matsuo, Kanade Shimizu, Osamu Shibahara, Michiko Fujiwara, Hiroki Kakuta, Sohei Ito, Teikichi Ikura, Nobutoshi Ito, Hiroaki Tokiwa
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Journal Title
FEBS Letters
Volume: 593(2)
Issue: 15
Pages: 242-250
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Presentation] Molecular origin of dual functionalities of fluorescent RXR agonists, CU-6PMN, which would be a key element for a high-throughput screening system of RXR ligands based on fluorescent intensity assay2019
Author(s)
Mayu Kawasaki, Shogo Nakano, Tomoharu Motoyama, Shoya Yamada, Masaki Watanabe, Michiko Fujihara, Hiroaki Tokiwa, Hiroki Kakuta, Sohei Ito
Organizer
ACS Fall 2019 National Meeting
Related Report
Int'l Joint Research
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[Presentation] In silico analysis on structure and function of lipid-metabolism related proteins based on the first-principles calculation2019
Author(s)
Hiroaki Tokiwa, Sundaram Arulmozhiraja, Vladimir Sladek, Yuta Yamamoto, Kanade Shimizu, Ryuhei Harada, Mitsuo Shoji, Yasuteru Shigeta, Yoshimi Nakagawa, Takeshi Matsuzaka, and Hitoshi Shimano
Organizer
11th symposium on Discovery, Fusion, Creation of New Knowledge by Multidisciplinary Computational Sciences, CCS International Symposium
Related Report
Int'l Joint Research
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[Presentation] Data Analysis Toolkits of Fragment Molecular Orbital Calculations to Visualize Interaction Energies Using the GUI Plugin for PyMOL2018
Author(s)
Takaki Tokiwa, Shogo Nakano, Yuta Yamamoto, Takeshi Ishikawa, Sohei Ito, Kaori Fukuzawa, Yuji Mochizuki, Hiroaki Tokiwa, Yasuteru Shigeta
Organizer
Chem-Bio Informatics Society(CBI) Annual Meeting 2018, Funabori, Japan
Related Report
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[Presentation] The extreme N-terminus of SLAM determines the fate of humans and monkeys against canine distemper virus infection2018
Author(s)
Fumio Seki, Hideo Fukuhara, Yuta Yamamoto, Sundaram Alulmozhiraja, Shogo Nakano, Sohei Ito, Kazue Ohishi, Tadashi Maruyama, Shigeru Morikawa, Ryoji Yamaguchi, Hiroaki Tokiwa, Katsumi Maenaka, Makoto Takeda
Organizer
The 17th Awaji International Forum on Infection and Immunity, Awajishima, Japan
Related Report
Int'l Joint Research
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[Presentation] How to design artificial protein surpassing native enzyme function similar to Design and multidisciplinary analysis of artificial L-threonine 3-dehydrogenase2018
Author(s)
Shogo Nakano, Tomoharu Motoyama, Yurina Miyashita, Yuki Ishizuka, Naoya Matsuo, Hiroaki Tokiwa, Suguru Shinoda, Yasuhisa Asano, Sohei Ito
Organizer
ASBMB Experimental Biology 2018 (San Diego, California), USA
Related Report
Int'l Joint Research
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[Presentation] What is the origin of partial agonist activity of CBt-PMN for hRXRα?2018
Author(s)
Kanade Shimizu, Yurina Miyashita, Yuta Yamamoto, Naoya Matsuo, Shogo Nakano, Sohei Ito, Nobutaka Numoto, Nobutoshi Ito, Hiroki Kakuta, Hiroaki Tokiwa
Organizer
ASBMB Experimental Biology 2018 (San Diego, California), USA
Related Report
Int'l Joint Research
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[Presentation] Computational design and molecular mechanism in oligomerization of C-terminal binding protein 22018
Author(s)
Yurina Miyashita, Naoya Matsuo, Yuta Yamamoto, Shogo Nakano, Sohei Ito, Nobutaka Numoto, Teikichi Ikura, Nobutoshi Ito, Motohiro Sekiya, Hitoshi Shimano, and Hiroaki Tokiwa
Organizer
ASBMB Experimental Biology 2018 (San Diego, California), USA
Related Report
Int'l Joint Research
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[Presentation] Crystal structure of the tetrameric ligand binding domain of RXRalpha complexed with a novel synthetic partial agonist.2018
Author(s)
Yurina Miyashita, Nobutaka Numoto, Sundaram Arulmozhiraja, Shogo Nakano, Naoya Matsuo, Kanade Shimizu, Osamu Shibahara, Michiko Fujiwara, Hiroki Kakuta, Sohei Ito, Teikichi Ikura, Nobutoshi Ito, Hiroaki Tokiwa
Organizer
The 56th Annual Meeting of the Biophysical Society of Japan (Okayama, Japan)
Related Report
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[Presentation] Role for the extreme N-terminus of SLAM in determination of the moribillivirus host range2018
Author(s)
Fumio Seki, Hideo Fukuhara, Yuta Yamamoto, Sundaram Alulmozhiraja, Shogo Nakano, Sohei Ito, Kazue Ohishi, Tadashi Maruyama, Shigeru Morikawa, Ryoji Yamaguchi, Hiroaki Tokiwa, Katsumi Maenaka, Makoto Takeda
Organizer
The 66th Annual Meeting of the Japansese Society of Viroglogy, Kyoto, Japan
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[Presentation] Computational design and molecular mechanism in oligomerization of C-terminal binding protein 22018
Author(s)
Miyashita, Y., Yamamoto, Y., Nakano, S., Ito, S., Numoto, N., Ikura, T., Ito, N., Sekiya, M., Shimano, H., Tokiwa, H.
Organizer
ASBMB2018
Related Report
Int'l Joint Research
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[Presentation] How to design artificial protein surpassing native enzyme function ~Design and multidisciplinary analysis of artificial L-threonine 3-dehydrogenase~2018
Author(s)
Nakano, S., Motoyama, T., Miyashita, Y., Ishizuka, Y., Matsuo, N., Tokiwa, H., Shinoda, S., Asano, Y., Ito, S.
Organizer
ASBMB2018
Related Report
Int'l Joint Research
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[Presentation] Discovery of novel monomeric L-threonine 3-dehydrogenase and elucidation of product release mechanism2018
Author(s)
Motoyama, T., Nakano, S., Yamamoto, Y., Tokiwa, H., Asano, Y., Ito, S.
Organizer
ASBMB2018
Related Report
Int'l Joint Research
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[Presentation] What is the origin of partial agonist activity of CBt-PMN for hRXRα?2018
Author(s)
Shimizu, K., Miyashita, Y., Matsuo, N., Yamamoto, Y., Nakano, S., Ito, S., Numoto, N., Ikura, T., Ito, N., Kakuta, H., Tokiwa, H.
Organizer
ASBMB2018
Related Report
Int'l Joint Research
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[Presentation] Molecular association model of Peroxisome Proliferator-Activated Receptor α and its new specific and efficient ligand, K-8772017
Author(s)
Miyashita, Y., Takei, K., Sladek, V., Nakano S., Ito, S., Matsuzaka, T., Sekiya, M., Nakagawa, Y., Tokiwa, H., Shimano, H.
Organizer
6th FIP Pharmaceutical Sciences World Congress 2017
Related Report
Int'l Joint Research
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[Presentation] Rational drug design of antiviral compounds using a novel in silico approach combining quantum chemistry and bioinformatics2017
Author(s)
Matsuo, N., Miyashita, Y., Nakano, S., Ito S., von Itzstein, M., Tokiwa, H.
Organizer
6th FIP Pharmaceutical Sciences World Congress 2017
Related Report
Int'l Joint Research
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[Presentation] Molecular basis of ligand interaction of GPR40/GPR120 based on FMO calculations with multiple sequence analysis2017
Author(s)
Yamamoto, Y., Sladek, V., Arulmozhiraja, S., Hayamizu, K., Nakano, S., Ito, S., Watanabe, Y., Yamada, S., Tokiwa, H.
Organizer
1th Triennial Congress of the World Association of Theoretical and Computational Chemists (WATOC 2017)
Related Report
Int'l Joint Research
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[Presentation] IN SILICO BINDING ANALYSIS OF NOVEL SEECTIVE PEROXISOME PROLIFERATOR-ACTIVATED RECPTORα MODULALTORS (SPPARMα)2017
Author(s)
Yamamoto, Y., Sladek, V., Takei, K., Nakagawa, Y., Shimano, H., Tokiwa, H.
Organizer
The 11th European Conference on Theoretical and Computational Chemistry EUCO-TCC
Related Report
Int'l Joint Research
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[Presentation] IN SILICO BINDING ANALYSIS OF PGC-1α INTERACTION WITH PEROXISOME PROLIFERATOR-ACTIVATED RECPTORα MODULALTORS2017
Author(s)
Sladek, V., Yamamoto, Y., Takei, K., Nakagawa, Y., Shimano, H., Tokiwa, H.
Organizer
The 11th European Conference on Theoretical and Computational Chemistry EUCO-TCC
Related Report
Int'l Joint Research
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[Presentation] Elucidating coevolution mechanism of morbillivirus with mammals using the fourth revolutionary method based on a novel protein multiple sequence method2017
Author(s)
Matsuo, N., Nakano, S., Ito, S., Seki, F., Takeda, M., Tokiwa, H.
Organizer
The 16th Awaji International Forum on Infection and Immunity
Related Report
Int'l Joint Research
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[Presentation] Computational Study of Enzyme Reaction Mechanism in monomeric L-threonine 3-dehydrogenase2017
Author(s)
Yamamoto, Y., Motoyama, T., Sladek, V., Stanislav, K., Nakano, S., Ito, S., Tokiwa, H.
Organizer
CPMD2017 conference
Related Report
Int'l Joint Research
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