Development and characterization of small molecules that regulate clock protein function for analysis of the circadian clock mechanism

• Project/Area Number: 15H05590
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Functional biochemistry
• Research Institution: Nagoya University
• Principal Investigator: Hirota Tsuyoshi 名古屋大学, トランスフォーマティブ生命分子研究所, 特任准教授 (50372412)
• Research Collaborator: ITAMI Kenichiro 名古屋大学, トランスフォーマティブ生命分子研究所, 教授 ; Jeffery Bode 名古屋大学, トランスフォーマティブ生命分子研究所, 教授 ; SATO Ayato 名古屋大学, トランスフォーマティブ生命分子研究所, 特任准教授 ; KUWATA Keiko 名古屋大学, トランスフォーマティブ生命分子研究所, 特任助教
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥23,530,000 (Direct Cost: ¥18,100,000、Indirect Cost: ¥5,430,000); Fiscal Year 2017: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2016: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2015: ¥10,530,000 (Direct Cost: ¥8,100,000、Indirect Cost: ¥2,430,000)
• Keywords: 概日時計 / 時計タンパク質 / PER / CRY / タンパク質分解 / タンパク質相互作用 / 低分子化合物 / ケミカルバイオロジー / 遺伝子 / 蛋白質 / 細胞・組織 / 発現制御 / 薬理学

Outline of Final Research Achievements

The circadian clock regulates daily rhythms of physiological processes through temporal and spatial organization from molecular to organismal levels. In this study, we focused on stability and complex formation of the clock proteins PER and CRY that play central role in the regulation of circadian period. We searched for regulatory compounds targeting these processes and discovered new compound that selectively control CRY1 function. In parallel, we analyzed post-translational modification of clock proteins by SUMO and identified CRY SUMOylation. By using original tools, we are going to reveal and control the molecular mechanism of the circadian clock.

Research Products

• [Journal Article] Conformational dynamics of human protein kinase CK2α and its effect on function and inhibition (2018)
  • Author(s): Ashutosh Srivastava, Tsuyoshi Hirota, Stephan Irle and Florence Tama
  • Journal Title: Proteins Structure Function and Genetics Volume: 86 Issue: 3 Pages: 344-353
  • DOI: 10.1002/prot.25444
  • NAID: 120006477488
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Global rise of potential health hazards caused by blue light-induced circadian disruption in modern aging societies. (2017)
  • Author(s): Hatori,M., Gronfier, C., Van Gelder, R.N., Bernstein, P.S., Carreras, J., Panda, S., Marks, F., Sliney, D., Hunt, C.E., Hirota, T., Furukawa, T. and Tsubota, K.
  • Journal Title: NPJ Aging Mech. Dis. Volume: 3 Issue: 1 Pages: 9-9
  • DOI: 10.1038/s41514-017-0010-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Circadian amplitude regulation via FBXW7-targeted REV-ERBa degradation (2016)
  • Author(s): Zhao, X., Hirota, T., Han, X., Cho, H., Chong, L., Lamia, K., Liu, S., Atkins, A.R., Banayo, E., Liddle, C., Yu, R.T., Yates III, J.R., Kay, S.A., Downes, M., and Evans, R.M.
  • Journal Title: Cell Volume: 165 Issue: 7 Pages: 1644-1657
  • DOI: 10.1016/j.cell.2016.05.012
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Heat shock factors modulate circadian rhythms (2016)
  • Author(s): Hirota, T., Fukada, Y.
  • Journal Title: Heat Shock Factor (Nakai, A. ed.) Volume: 1 Pages: 197-209
  • DOI: 10.1007/978-4-431-55852-1_10
  • ISBN: 9784431558507, 9784431558521
• [Journal Article] C-H Activation Generates Period-Shortening Moleculaes That Target Cryptochrome in the Mammalian Circadian Clock. (2015)
  • Author(s): Oshima T, Yamanaka I, Kumar A, Yamaguchi J, Nishiwaki-Okawa T, Muto K, Kawamura R, Hirota T, Yagita K, Irie S, Kay SA, Yoshimura T, Itami K.
  • Journal Title: Angew Chem Int Ed Volume: 54 Issue: 24 Pages: 7193-7197
  • DOI: 10.1002/anie.201502942
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Development of small molecule Cryptochrome stabilizer derivatives as modulators of the circadian clock. (2015)
  • Author(s): Lee, J.W.*, Hirota, T.*,# (*, equal contribution; #, correspondence), Kumar, A.*,#, Kim, N.J., Irle, S., and Kay, S.A.#
  • Journal Title: ChemMedChem Volume: 10 Issue: 9 Pages: 1489-1497
  • DOI: 10.1002/cmdc.201500260
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Identification of CRY1/CRY2 selective compounds (2018)
  • Author(s): Aikawa, Y. Kay, S.A., Hirota, T.
  • Organizer: 12th Annual Salk Institute, Fondation IPSEN, and Science Symposium on Biological Complexity
  • Int'l Joint Research
• [Presentation] Chemical and structural biology approaches to understand molecular mechanism underlying 24-hour period of mammalian circadian clock (2017)
  • Author(s): Hirota, T.
  • Organizer: 第55回日本生物物理学会年会
  • Invited
• [Presentation] ケミカルバイオロジーによる24時間の創出原理の分子研究 (2017)
  • Author(s): 廣田 毅
  • Organizer: 第24回日本時間生物学会学術大会
  • Invited
• [Presentation] Dissecting design principal of biological clock by using chemical tools (2017)
  • Author(s): Hirota, T.
  • Organizer: MANA International Symposium 2017
  • Place of Presentation: Tsukuba
  • Int'l Joint Research / Invited
• [Presentation] Chemical regulation of the molecular clock (2016)
  • Author(s): Hirota, T.
  • Organizer: The 29th Conference of the International Society for Chronobiology
  • Place of Presentation: Suzhou, China
  • Int'l Joint Research / Invited
• [Presentation] 化学と生物学の融合による時間生物学研究 (2016)
  • Author(s): 廣田 毅
  • Organizer: 第23回日本時間生物学会学術大会
  • Place of Presentation: 名古屋
  • Invited
• [Presentation] 概日時計タンパク質CRYのFAD結合ポケットに作用する低分子化合物の発見 (2015)
  • Author(s): 廣田 毅
  • Organizer: BMB2015
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] 哺乳類の概日時計分子のケミカルバイオロジーと構造生物学 (2015)
  • Author(s): 廣田 毅
  • Organizer: 蛋白研セミナー「第６回 神経科学と構造生物学の融合研究会」
  • Place of Presentation: 岡崎
  • Year and Date: 2015-11-27
  • Invited
• [Presentation] Chrono-nutrition研究における細胞ベースのハイスループットアッセイ (2015)
  • Author(s): 廣田 毅
  • Organizer: 第22回日本時間生物学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2015-11-22
  • Invited
• [Remarks] 名古屋大学トランスフォーマティブ生命分子研究所Kay-廣田グループ
  • URL: http://www.itbm.nagoya-u.ac.jp/ja/kay-hirota_group/
• [Remarks] 名古屋大学トランスフォーマティブ生命分子研究所 Kay-廣田グループ
  • URL: http://www.itbm.nagoya-u.ac.jp/ja/kay-hirota_group/