Structural elucidation of dioxin recognition by aryl hydrocarbon receptor

• Project/Area Number: 15K14471
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Functional biochemistry
• Research Institution: The University of Tokyo
• Principal Investigator: Ohto Umeharu 東京大学, 大学院薬学系研究科(薬学部), 准教授 (90451856)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: ダイオキシン / 環境ホルモン / 構造生物学 / Ｘ線結晶構造解析 / Ｘ線結晶解析

Outline of Final Research Achievements

We conducted the structural biology of aryl hydrocarbon receptor (AhR), known as dioxin receptor. We tried to prepare the pre-nuclear translocation complex of AhR but it was not successful. We conducted the crystallization of the AhR inhibitory complex, AhRR/ARNT complex, and determined its crystal structure. To obtain the structural information of the AhR transcriptional activation complex, AhR/ARNT complex, we tried to prepare AhR/ARNT complex derived from various organism species, and expressed and purified various mutants of AhR/ARNT.

Research Products

• [Int'l Joint Research] ミネソタ大/コロラド大(米国)
• [Int'l Joint Research] ミネソタ大学/カンザス大学(米国)
• [Journal Article] The crystal structure of mouse LC3B in complex with the FYCO1 LIR reveals the importance of the flanking region of the LIR motif. (2017)
  • Author(s): Sakurai S, Tomita T, Shimizu T, Ohto U
  • Journal Title: Acta Crystallographica Section F Volume: 73 Issue: 3 Pages: 130-137
  • DOI: 10.1107/s2053230x17001911
  • Peer Reviewed
• [Journal Article] Emerging roles of the processing of nucleic acids and Toll-like receptors in innate immune responses to nucleic acids (2017)
  • Author(s): Miyake K, Shibata T, Ohto U, Shimizu T
  • Journal Title: J Leukoc Biol Volume: 101 Issue: 1 Pages: 135-142
  • DOI: 10.1189/jlb.4mr0316-108r
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Structural Analysis Reveals that Toll-like Receptor 7 Is a Dual Receptor for Guanosine and Single-Stranded RNA (2016)
  • Author(s): Zhang Z, Ohto U, Shibata T, Krayukhina E, Taoka M, Yamauchi Y, Tanji H, Isobe T, Uchiyama S, Miyake K, Shimizu T
  • Journal Title: Immunity Volume: 45 Issue: 4 Pages: 737-748
  • DOI: 10.1016/j.immuni.2016.09.011
  • Peer Reviewed
• [Journal Article] Crystal structure of NOD2 and its implications in human disease. (2016)
  • Author(s): Maekawa S, Ohto U, Shibata T, Miyake K, Shimizu T
  • Journal Title: Nat Commun Volume: 7 Issue: 1 Pages: 11813-11813
  • DOI: 10.1038/ncomms11813
  • Peer Reviewed / Open Access
• [Journal Article] Identification of a Human Toll-Like Receptor (TLR) 8-Specific Agonist and a Functional Pan-TLR Inhibitor in 2-Aminoimidazoles. (2016)
  • Author(s): Beesu, M., Caruso, G., Salyer, A. C., Shukla, N. M., Khetani, K. K., Smith, L. J., Fox, L. M., Tanji, H., Ohto, U., Shimizu, T., & David, S. A.
  • Journal Title: J. Med. Chem. Volume: 59 Issue: 7 Pages: 3311-3330
  • DOI: 10.1021/acs.jmedchem.6b00023
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Autoinhibition and relief mechanism by the proteolytic processing of Toll-like receptor 8. (2016)
  • Author(s): Tanji, H., Ohto, U., Motoi, Y., Shibata, T., Miyake, K., & Shimizu, T.
  • Journal Title: Proc. Natl. Acad. Sci. U S A Volume: 113 Issue: 11 Pages: 3012-3017
  • DOI: 10.1073/pnas.1516000113
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Eritoran inhibits S100A8-mediated TLR4/MD-2 activation and tumor growth by changing the immune microenvironment. (2016)
  • Author(s): Deguchi A, Tomita T, Ohto U, Takemura K, Kitao A, Akashi-Takamura, S, Miyake K, and Maru Y.
  • Journal Title: Oncogene Volume: 35 Issue: 11 Pages: 1445-1456
  • DOI: 10.1038/onc.2015.211
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Structure-based Design of Human TLR8-specific Agonists with Augmented Potency and Adjuvanticity. (2015)
  • Author(s): Beesu, M., Caruso, G., Salyer, A., Khetani, K., Sil, D., Weerasinghe, M., Tanji, H., Ohto, U., Shimizu, T., & David, S. A.
  • Journal Title: J. Med. Chem. Volume: 58 Issue: 19 Pages: 7833-7849
  • DOI: 10.1021/acs.jmedchem.5b01087
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The Imidazoquinoline Toll-Like Receptor-7/8 Agonist Hybrid-2 Potently Induces Cytokine Production by Human Newborn and Adult Leukocytes. (2015)
  • Author(s): Ganapathi, L., Van Haren, S., Dowling, D. J., Bergelson, I., Shukla, N. M., Malladi, S. S., Balakrishna, R., Tanji, H., Ohto, U., Shimizu, T., David, S. A., & Levy, O.
  • Journal Title: PLoS One Volume: 10 Issue: 8 Pages: 0134640-0134640
  • DOI: 10.1371/journal.pone.0134640
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Structure of human Roquin-2 and its complex with constitutive-decay element RNA. (2015)
  • Author(s): Sakurai, S., Ohto, U., & Shimizu, T.
  • Journal Title: Acta Crystallogr. Sect. F Volume: 71 Issue: 8 Pages: 1048-1054
  • DOI: 10.1107/s2053230x15011887
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Structures of nucleic acids sensing Toll-like receptors (2016)
  • Author(s): Umeharu Ohto and Toshiyuki Shimizu
  • Organizer: The 45th annual meeting of the Japanese Society for Immunology (JSI)（
  • Place of Presentation: 沖縄コンベンションセンター（沖縄、宜野湾）
  • Year and Date: 2016-12-05
  • Invited
• [Presentation] Structural studies of innate immune RNA receptor human TLR8 (2016)
  • Author(s): Hiromi Tanji, Umeharu Ohto, Toshiyuki Shimizu
  • Organizer: 14th Conference of the Asian Crystallographic Association
  • Place of Presentation: Hanoi, Vietnam
  • Year and Date: 2016-12-04
  • Int'l Joint Research
• [Presentation] 自然免疫受容体 TLR7 の構造学的研究 (2016)
  • Author(s): 張志寛、大戸梅治、清水敏之
  • Organizer: 第16回日本蛋白質科学会年会
  • Place of Presentation: 福岡国際会議場（福岡、博多）
  • Year and Date: 2016-06-07
• [Presentation] 核酸認識Toll様受容体によるリガンド認識とシグナル伝達の構造基盤 (2015)
  • Author(s): 大戸梅治、清水敏之
  • Organizer: BMB2015 第38回日本分子生物学会年会 第88回日本生化学会大会 合同大会
  • Place of Presentation: 神戸ポートアイランド（神戸）
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] mRNA分解に関与するタンパク質Roquin-2とRNA複合体のX線結晶構造解析 (2015)
  • Author(s): 櫻井駿也、大戸梅治、清水敏之
  • Organizer: 平成27年度日本結晶学会
  • Place of Presentation: 大阪府立大学（大阪）
  • Year and Date: 2015-10-17
• [Presentation] Structural studies of single-stranded RNA receptor TLR8 (2015)
  • Author(s): Hiromi Tanji, Umeharu Ohto, Takuma Shibaga, Kensuke Miyake, Toshiyuki Shimizu
  • Organizer: Toll meeting 2015
  • Place of Presentation: Marbella, Spain
  • Year and Date: 2015-09-30
  • Int'l Joint Research
• [Presentation] Crystallographic analyses of Toll-like receptor 9 recognizing CpG DNA (2015)
  • Author(s): U. Ohto, T. Shibata, H. Tanji, H. Ishida, E. Krayukhina, S. Uchiyama, K. Miyake, and T. Shimizu
  • Organizer: Toll meeting 2015
  • Place of Presentation: Marbella, Spain
  • Year and Date: 2015-09-30
• [Presentation] Ligand recognition and signal transduction by Toll-like receptor (2015)
  • Author(s): Umeharu Ohto
  • Organizer: 第53回日本生物物理学会
  • Place of Presentation: 金沢大学（金沢）
  • Year and Date: 2015-09-13
  • Int'l Joint Research
• [Presentation] 自然免疫受容体NOD2の構造学的研究 (2015)
  • Author(s): 前川早貴子、大戸梅治、清水敏之
  • Organizer: 第15回日本蛋白質科学会年会
  • Place of Presentation: あわぎんホール（徳島）
  • Year and Date: 2015-06-24
• [Presentation] 自然免疫系一本鎖RNA受容体TLR8の構造基盤 (2015)
  • Author(s): 丹治裕美、大戸梅治、柴田琢磨、田岡万悟、山内芳雄、礒邉俊明、三宅健介、清水敏之
  • Organizer: 第15回日本蛋白質科学会年会
  • Place of Presentation: あわぎんホール（徳島）
  • Year and Date: 2015-06-24
• [Remarks] 研究室ホームページ
  • URL: http://www.f.u-tokyo.ac.jp/~kouzou/index.html