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Structural basis of proteins related with innate immunity

Research Project

Project/Area Number 16H02494
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Structural biochemistry
Research InstitutionThe University of Tokyo

Principal Investigator

Shimizu Toshiyuki  東京大学, 大学院薬学系研究科(薬学部), 教授 (30273858)

Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥43,290,000 (Direct Cost: ¥33,300,000、Indirect Cost: ¥9,990,000)
Fiscal Year 2018: ¥11,570,000 (Direct Cost: ¥8,900,000、Indirect Cost: ¥2,670,000)
Fiscal Year 2017: ¥13,260,000 (Direct Cost: ¥10,200,000、Indirect Cost: ¥3,060,000)
Fiscal Year 2016: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000)
Keywords自然免疫 / X線結晶構造解析 / Nod様受容体 / Toll様受容体 / TLR / X線結晶解析 / 構造生物 / X線解析 / NLR
Outline of Final Research Achievements

Innate immunity serves as the first line of defense against invading pathogens such as bacteria and viruses, and active adaptive immunity. We focused on the innate immune proteins, and tried to reveal the ligand recognition and regulation mechanisms by structural studies.
We determined the crystal structure of rabbit NOD2 in an ADP-bound state. The structure reveals an inactive closed conformation. We found a hydrophobic pocket on the concave surface of the LRR domain, suitable for accommodating glycan or peptide moieties of MDP. Structural studies of TLR sensing a single-stranded nucleic acids (TLR7, 8, 9) revealed that these TLRs share common mechanism for activation mechanism. Roquin mediates mRNA degradation by recognizing the constitutive-decay element (CDE) followed by recruitment of the deadenylation machinery. Crystal structure of Roquin-RNA complex revealed that The CDE RNA, forming a stem-loop structure, bound to the positively charged surface of the ROQ domain.

Academic Significance and Societal Importance of the Research Achievements

NLRの構造は数例に限られており、NOD2の構造情報はNLRの活性化機構を解明するうえで重要な情報となる。一本鎖核酸を認識するTLRが有する共通性「リガンド結合部位が2ヶ所あり別々のリガンドが各部位に結合することにより協調的に活性化する」を解明したことは大きなインパクトを与えた。特にTLR7,8は低分子化合物によって活性化されることが知られており、立体構造情報はあらたな化合物開発に多大な貢献を示すと考えられる。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (22 results)

All 2018 2017 2016 Other

All Journal Article (15 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 15 results,  Open Access: 5 results,  Acknowledgement Compliant: 4 results) Presentation (5 results) (of which Int'l Joint Research: 3 results,  Invited: 4 results) Remarks (2 results)

  • [Journal Article] Toll-like Receptor 9 Contains Two DNA Binding Sites that Function Cooperatively to Promote Receptor Dimerization and Activation2018

    • Author(s)
      Ohto Umeharu、Ishida Hanako、Shibata Takuma、Sato Ryota、Miyake Kensuke、Shimizu Toshiyuki
    • Journal Title

      Immunity

      Volume: 48 Issue: 4 Pages: 649-658

    • DOI

      10.1016/j.immuni.2018.03.013

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Structural basis for species-specific activation of mouse Toll-like receptor 92018

    • Author(s)
      Ishida Hanako、Ohto Umeharu、Shibata Takuma、Miyake Kensuke、Shimizu Toshiyuki
    • Journal Title

      FEBS Letters

      Volume: 592 Issue: 15 Pages: 2636-2646

    • DOI

      10.1002/1873-3468.13176

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mechanisms controlling nucleic acid-sensing Toll-like receptors2018

    • Author(s)
      Miyake Kensuke、Shibata Takuma、Ohto Umeharu、Shimizu Toshiyuki、Saitoh Shin-Ichiroh、Fukui Ryutaro、Murakami Yusuke
    • Journal Title

      International Immunology

      Volume: 30 Issue: 2 Pages: 43-51

    • DOI

      10.1093/intimm/dxy016

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Structural Analyses of Toll-like Receptor 7 Reveal Detailed RNA Sequence Specificity and Recognition Mechanism of Agonistic Ligands2018

    • Author(s)
      Zhang Zhikuan、Ohto Umeharu、Shibata Takuma、Taoka Masato、Yamauchi Yoshio、Sato Ryota、Shukla Nikunj M.、David Sunil A.、Isobe Toshiaki、Miyake Kensuke、Shimizu Toshiyuki
    • Journal Title

      Cell Reports

      Volume: 25 Issue: 12 Pages: 3371-3381

    • DOI

      10.1016/j.celrep.2018.11.081

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Small-Molecule TLR8 Antagonists via Structure-Based Rational Design2018

    • Author(s)
      Hu Zhenyi、Tanji Hiromi、Jiang Shuangshuang、Zhang Shuting、Koo Kyoin、Chan Jean、Sakaniwa Kentaro、Ohto Umeharu、Candia Albert、Shimizu Toshiyuki、Yin Hang
    • Journal Title

      Cell Chemical Biology

      Volume: 25 Issue: 10 Pages: 1286-1291

    • DOI

      10.1016/j.chembiol.2018.07.004

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Small-molecule inhibition of TLR8 through stabilization of its resting state2018

    • Author(s)
      Zhang, S., Hu, Z., Tanji, H., Jiang, S., Das, N, Li, J., Sakaniwa, K., Jin, J., Bian, Y., Ohto, U., Shimizu, T., Yin, H.
    • Journal Title

      Nature Chem. Biol.

      Volume: 14 Issue: 1 Pages: 58-64

    • DOI

      10.1038/nchembio.2518

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] The crystal structure of the AhRR-ARNT heterodimer reveals the structural basis of the repression of AhR-mediated transcription2017

    • Author(s)
      Sakurai, S., Shimizu, T., & *Ohto, U.
    • Journal Title

      J. Biol. Chem.

      Volume: 292 Issue: 43 Pages: 17609-17616

    • DOI

      10.1074/jbc.m117.812974

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Towards a structural understanding of nucleic acid-sensing Toll-like receptors in the innate immune system2017

    • Author(s)
      Zhang Z, Ohto U, Shimizu T
    • Journal Title

      FEBS letters

      Volume: 591 Pages: 3167-3181

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Structural insights into ligand recognition and regulation of nucleic acid-sensing Toll-like receptors2017

    • Author(s)
      Shimizu T
    • Journal Title

      Curr. Opi. Struc. Biol.

      Volume: 47 Pages: 52-59

    • DOI

      10.1016/j.sbi.2017.05.010

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Emerging roles of the processing of nucleic acids and Toll-like receptors in innate immune responses to nucleic acids2017

    • 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

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Structural Analysis Reveals that Toll-like Receptor 7 Is a Dual Receptor for Guanosine and Single-Stranded RNA2016

    • 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

    • Related Report
      2016 Annual Research Report
    • 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

    • Related Report
      2016 Annual Research Report
    • 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

    • Related Report
      2016 Annual Research Report
    • 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

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Guanosine and its modified derivatives are endogenous ligands for TLR72016

    • Author(s)
      Shibata T, Ohto U, Nomura S, Kibata K, Motoi Y, Zhang Y, Murakami Y, Fukui R, Ishimoto T, Sano S, Ito T, Shimizu T, Miyake K.
    • Journal Title

      Int Immunol

      Volume: - Issue: 5 Pages: 211-222

    • DOI

      10.1093/intimm/dxv062

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Presentation] 構造解析から見えた自然免疫における一本鎖核酸認識 Toll様受容体の共通性およびその創薬への展開2018

    • Author(s)
      清水敏之
    • Organizer
      ゲノム創薬・医療フォーラム
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 病原体感染を感知するToll様受容体の構造基盤2018

    • Author(s)
      清水敏之
    • Organizer
      日本薬学会 第138年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Structural study of ssRNA sensing TLRs in innate immune system2017

    • Author(s)
      Toshiyuki Shimizu
    • Organizer
      24th Congress and General Assembly of the International Union of Crystallography
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Structural study of TLRs sensing single stranded RNA in innate immune system2016

    • Author(s)
      Toshiyuki Shimizu
    • Organizer
      Naito Conference
    • Place of Presentation
      Chateraise Gateaux Kingdom Sapporo(北海道、札幌市)
    • Year and Date
      2016-10-04
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Structural basis of CpG and inhibitory DNA recognition by Toll-like receptor 92016

    • Author(s)
      Toshiyuki Shimizu
    • Organizer
      12th Annual Meeting of the Oligonucleotide Therapeutics Society
    • Place of Presentation
      Centre Mont-Royal (Montreal, Canada)
    • Year and Date
      2016-09-25
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Remarks]

    • URL

      http://www.f.u-tokyo.ac.jp/~kouzou/index.html

    • Related Report
      2017 Annual Research Report
  • [Remarks]

    • URL

      http://www.f.u-tokyo.ac.jp/~kouzou/

    • Related Report
      2016 Annual Research Report

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Published: 2016-04-21   Modified: 2020-03-30  

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