Non-equilibrium-state molecular movies and their applications

• Project Area: Non-equilibrium-state molecular movies and their applications
• Project/Area Number: 19H05776
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Complex systems
• Research Institution: Kyoto University
• Principal Investigator: Iwata So 京都大学, 医学研究科, 教授 (60452330)
• Project Period (FY): 2019-06-28 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥61,620,000 (Direct Cost: ¥47,400,000、Indirect Cost: ¥14,220,000); Fiscal Year 2023: ¥12,090,000 (Direct Cost: ¥9,300,000、Indirect Cost: ¥2,790,000); Fiscal Year 2022: ¥12,090,000 (Direct Cost: ¥9,300,000、Indirect Cost: ¥2,790,000); Fiscal Year 2021: ¥12,090,000 (Direct Cost: ¥9,300,000、Indirect Cost: ¥2,790,000); Fiscal Year 2020: ¥12,090,000 (Direct Cost: ¥9,300,000、Indirect Cost: ¥2,790,000); Fiscal Year 2019: ¥13,260,000 (Direct Cost: ¥10,200,000、Indirect Cost: ¥3,060,000)
• Keywords: 構造生物学 / 計算科学 / ケミカルバイオロジー / ビームラインテクノロジー / 光薬理学 / 光遺伝学 / 分光学 / 動的構造解析 / 分子動画 / X線自由電子レーザー / 生体高分子 / 分子制御 / 総括班 / 高速分子動画 / タンパク質 / 構造解析

Outline of Research at the Start

生命現象を支えているタンパク質の機能やその機構を理解するためには、タンパク質の中で実際におこっている化学変化や構造変化を追跡することが不可欠である。X線自由電子レーザーを用いて、タンパク質の中で起こる非常に早い化学反応等を他の手法では全く考えられない時間分解能と空間分解能を併せ持った“分子動画”として観察する手法の開発を推進する。本法を多種多様なタンパク質に適用できる汎用的技術として確立するために分野融合的に開発を進め、光によるタンパク質のスイッチ機構の解明やユニークな反応を触媒する酵素の反応機構等の解明を目指し、分子制御への応用も展開する。総括班はそれら研究推進の核として研究活動を牽引する。

Outline of Final Research Achievements

In order to establish this method as a universal method applicable to the observation of more biological macromolecules, we have tried to remove as many limitations as possible from the “molecular movie” method by maximizing the use of beamline engineering, protein engineering, chemical biology, and other technologies. As a result, we succeeded in obtaining fast molecular movies of new proteins such as visual rhodopsin and DNA photolyase. Furthermore, we reported a quantitative and theoretical analysis of the observed molecular movies using computational and spectroscopic methods. Based on these results, we also developed new compounds that can control proteins and evaluated their properties. An international symposium was held to report and discuss these results.

Academic Significance and Societal Importance of the Research Achievements

本領域は単にタンパク質の分子動画を撮るだけではなく、タンパク質のダイナミックスを理解し、それに基づき新しい機能性タンパク質やタンパク質の機能を制御できる化合物を創生できる可能性を示した。今後は実際に光遺伝学に使える新規機能タンパク質や光薬理学に使えるツールを開発し、それらを基礎研究や臨床研究そして実際の治療法や新規薬物の開発につなげていきたい。

Research Products

• [Int'l Joint Research] ルーヴェンカトリック大学（KU-Leuven）(ベルギー)
• [Int'l Joint Research] Stockholm University(スウェーデン)
• [Int'l Joint Research] Academia Sinica(その他の国・地域(台湾）)
• [Int'l Joint Research] RC分子生物学研究所(英国)
• [Int'l Joint Research] ルーヴェンカトリック大学 (KU Leuven)(ベルギー)
• [Int'l Joint Research] Stockholm University(スウェーデン)
• [Int'l Joint Research] Academia Sinica(その他の国・地域(台湾))
• [Int'l Joint Research] RC分子生物学研究所(英国)
• [Int'l Joint Research] ルーヴェンカトリック大学 (KU Leuven)(ベルギー)
• [Int'l Joint Research] Academia Sinica(その他の国・地域(台湾))
• [Int'l Joint Research] 分子生物学研究所(英国)
• [Int'l Joint Research] Stockholm University(スウェーデン)
• [Int'l Joint Research] ルーヴェンカトリック大学 (KU Leuven)(ベルギー)
• [Int'l Joint Research] Academia Sinica(その他の国・地域（台湾）)
• [Int'l Joint Research] RC分子生物学研究所(英国)
• [Int'l Joint Research] Stockholm University(スウェーデン)
• [Int'l Joint Research] ルーヴェンカトリック大学 (KU Leuven)(ベルギー)
• [Int'l Joint Research] Academia Sinica(その他の国・地域（台湾）)
• [Int'l Joint Research] MRC分子生物学研究所(英国)
• [Int'l Joint Research] Stockholm University(スウェーデン)
• [Journal Article] Visualizing the DNA repair process by a photolyase at atomic resolution (2023)
  • Author(s): Manuel Maestre-Reyna, Po-Hsun Wang, Eriko Nango, Yuhei Hosokawa, Martin Saft , Antonia Furrer , Cheng-Han Yang , Eka Putra Gusti Ngurah Putu , Wen-Jin Wu, (…), So Iwata ,(…..) and Ming-Daw Tsai
  • Journal Title: Science (New York, N.Y.) Volume: Vol.382, No.6674 Issue: 6674
  • DOI: 10.1126/science.add7795
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mapping protein dynamics at high spatial resolution with temperature-jump X-ray crystallography (2023)
  • Author(s): Wolff, A. M., Nango, E., Young, I. D., Brewster, A. S., Kubo, M., Nomura, T., Sugahara, M., Owada, S., Barad, B. A., Ito, K., Bhowmick, A., Carbajo, S., Hino, T., Holton, J. M., Im, D., O'Riordan, L. J., Tanaka, T., Tanaka, R., Sierra, R. G., Yumoto, F., Tono, K., Iwata, S., et al
  • Journal Title: Nat. Chem. Volume: 15(11) Issue: 11 Pages: 1549-1558
  • DOI: 10.1038/s41557-023-01329-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Recent progress in membrane protein dynamics revealed by X-ray free electron lasers: Molecular movies of microbial rhodopsins (2023)
  • Author(s): Eriko Nango and So Iwata
  • Journal Title: Curr. Opin. Struct.Biol. Volume: 81 Pages: 102629-102629
  • DOI: 10.1016/j.sbi.2023.102629
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ultrafast structural changes direct the first molecular events of vision (2023)
  • Author(s): Gruhl T, Weinert T, Rodrigues M J, Milne C J, Ortolani G, Nass K, Nango E, ...Schertler G, and Panneels V. et al.
  • Journal Title: Nature Volume: 615 Issue: 7954 Pages: 939-944
  • DOI: 10.1038/s41586-023-05863-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Conformational alterations in unidirectional ion transport of a light-driven chloride pump revealed using X-ray free electron lasers. (2022)
  • Author(s): Hosaka, T. et al.
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 119 Issue: 9
  • DOI: 10.1073/pnas.2117433119
  • Peer Reviewed / Open Access
• [Journal Article] Lipidic cubic phase serial femtosecond crystallography structure of a photosynthetic reaction centre (2022)
  • Author(s): Bath P, Banacore A, Borjesson P, Iwata S, *Branden G and *Neutze R. et al.
  • Journal Title: Acta Crystallographica Section D Structural Biology Volume: 78 Issue: 6 Pages: 698-708
  • DOI: 10.1107/s2059798322004144
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Crystal structure of CmABCB1 multi-drug exporter in lipidic mesophase revealed by LCP-SFX (2021)
  • Author(s): Pan Dongqing、Oyama Ryo、Sato Tomomi、Nakane Takanori、Mizunuma Ryo、Matsuoka Keita、Joti Yasumasa、Tono Kensuke、Nango Eriko、Iwata So、Nakatsu Toru、Kato Hiroaki
  • Journal Title: IUCrJ Volume: 9 Issue: 1 Pages: 134-145
  • DOI: 10.1107/s2052252521011611
  • NAID: 120007179308
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Endogenous agonist?bound S1PR3 structure reveals determinants of G protein?subtype bias (2021)
  • Author(s): Maeda Shintaro、Shiimura Yuki、Asada Hidetsugu、Hirata Kunio、Luo Fangjia、Nango Eriko、Tanaka Nobuo、Toyomoto Masayasu、Inoue Asuka、Aoki Junken、Iwata So、Hagiwara Masatoshi
  • Journal Title: Science Advances Volume: 7 Issue: 24
  • DOI: 10.1126/sciadv.abf5325
  • NAID: 120007052733
  • Peer Reviewed / Open Access
• [Journal Article] S1PR3?G12-biased agonist ALESIA targets cancer metabolism and promotes glucose starvation (2021)
  • Author(s): Toyomoto Masayasu、Inoue Asuka、Iida Kei、Denawa Masatsugu、Kii Isao、Ngako Kadji Francois Marie、Kishi Takayuki、Im Dohyun、Shimamura Tatsuro、Onogi Hiroshi、Yoshida Suguru、Iwata So、Aoki Junken、Hosoya Takamitsu、Hagiwara Masatoshi
  • Journal Title: Cell Chemical Biology Volume: 未定 Issue: 8 Pages: 1132-1144
  • DOI: 10.1016/j.chembiol.2021.01.004
  • Peer Reviewed / Open Access
• [Journal Article] Structure of the dopamine D2 receptor in complex with the antipsychotic drug spiperone (2020)
  • Author(s): Im Dohyun、Inoue Asuka、Fujiwara Takaaki、Nakane Takanori、Yamanaka Yasuaki、Uemura Tomoko、Mori Chihiro、Shiimura Yuki、Kimura Kanako Terakado、Asada Hidetsugu、Nomura Norimichi、Tanaka Tomoyuki、Yamashita Ayumi、Nango Eriko、Tono Kensuke、Kadji Francois Marie Ngako、Aoki Junken、Iwata So、Shimamura Tatsuro
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 1-11
  • DOI: 10.1038/s41467-020-20221-0
  • NAID: 120006943309
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Four-dimensional structural analysis of membrane proteins and its application to drug discovery (2023)
  • Author(s): 岩田 想
  • Organizer: LEAPS Meets Life Sciences Conference
  • Int'l Joint Research / Invited
• [Presentation] 高速分子動画：これまでの成果と今後の展開 (2022)
  • Author(s): 岩田想
  • Organizer: 第95回日本生化学会大会
• [Presentation] 高速分子動画による構造ダイナミクス研究 (2022)
  • Author(s): 岩田想
  • Organizer: 第35回日本放射光学会年会・放射光科学合同シンポジウム
• [Presentation] 高速分子動画法とその分子制御への応用, Making Molecular Movies (2021)
  • Author(s): 岩田想
  • Organizer: 第77回顕微鏡学会学術講演会
• [Presentation] 抗体フラグメントを用いたGPCRの構造解析と創薬への応用 (2020)
  • Author(s): 岩田想
  • Organizer: 第93回日本生化学会大会
• [Funded Workshop] "Molecular Movies" International Symposium 2023; Molecular Movies to be continued (2023)
• [Funded Workshop] “Molecular Movies” International Symposium 2022 (2022)