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The mechanism of the inhibition of protein aggregation that causes conformational diseases by low-moleculer compunds

Research Project

Project/Area Number 19570155
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Biophysics
Research InstitutionOsaka Prefecture University

Principal Investigator

ONDA Maki  Osaka Prefecture University, 理学系研究科, 助教 (60311916)

Project Period (FY) 2007 – 2009
Project Status Completed (Fiscal Year 2009)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2008: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2007: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywordsセルピン / コンフォメーション病 / 認知症 / 神経変性 / フォールディング / 痴呆 / タンパク質の折りたたみ / リフォールディング / 凝集体形成 / 脳
Research Abstract

Neuroserpin is a neuronal protein predominantly expressed in the brain, and its mutants readily form aggregates that cause dementia. Several compounds that prevent aggregation of neuroserpin were found, and crystals of human neuroserpin were successfully obtained using them. The crystal structure was determined at 2.1Å, and interactions between the protein and the compound were analyzed. Furthermore, the compounds were effective in stabilizing a refolding intermediate of neuroserpin, which is promising for a target molecule in therapeutic drug design. Using the compounds, the intermediate was purified and characterized.

Report

(4 results)
  • 2009 Annual Research Report   Final Research Report ( PDF )
  • 2008 Annual Research Report
  • 2007 Annual Research Report
  • Research Products

    (27 results)

All 2010 2009 2008 2007 Other

All Journal Article (10 results) (of which Peer Reviewed: 10 results) Presentation (16 results) Remarks (1 results)

  • [Journal Article] pH-dependent stability of neuroserpin is mediated by histidines 119 and 138 ; Implications for the control of β-sheet A and polymerization2010

    • Author(s)
      Didier Belorgey
    • Journal Title

      Protein Science 19

      Pages: 220-228

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The 2. 1Åcrystal structure of native neuroserpin reveals unique structural elements that contribute to conformational instability.2009

    • Author(s)
      恩田真紀, 中谷和代, 竹原清日, 西山美香, 三上文三, D.A. Lomas
    • Journal Title

      Journal of Molecular Biology 388巻

      Pages: 11-20

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] pH dependent stability of neuroserpin is mediated by Histidines 119 and 138; implications for the control of beta-sheet A and polymerisation.2009

    • Author(s)
      Didier Belorgey, Peter Hagglof, 恩田真紀, David A. Lomas
    • Journal Title

      Protein Science 19巻

      Pages: 220-228

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] The 2.1-A crystal structure of native neuroserpin reveals unique structural elements that contribute to conformational instability.2009

    • Author(s)
      Sayaka Takehara
    • Journal Title

      Journal of Molecular Biology 388

      Pages: 11-20

    • Related Report
      2009 Annual Research Report 2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 解明されたミステリー : セルピン病の発症機構2009

    • Author(s)
      恩田 真紀
    • Journal Title

      蛋白質科学会アーカイブ 2

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cleaved serpin refolds into the relaxed state via a stressed conformer.2008

    • Author(s)
      恩田真紀, 中谷和代, 竹原清日, 西山美香, 高橋延行, 廣瀬正明
    • Journal Title

      The Journal of Biological Chemistry 283巻

      Pages: 17568-17578

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] Cleaved serpin refolds to the relaxed state via a stressed conformer.2008

    • Author(s)
      Maki Onda
    • Journal Title

      The Journal of Biological Chemistry 283

      Pages: 17568-17578

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Susceptibilities of phospholipid membranes containing cholesterol or ergosterol to gramicidin and its derivative incorporated in lysophospholipid micelles.2008

    • Author(s)
      Naoko Yoshida
    • Journal Title

      The Journal of Biochemistry 143

      Pages: 167-176

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cleaved serpin refolds to the relaxed state via a stressed conformer2008

    • Author(s)
      Maki Onda
    • Journal Title

      The Journal of Biological Chemistry 283(印刷中)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Susceptibilities of phospholipid membranes containing cholesterol or ergosterol to gramicidin and its derivative incorporated in lysohosholipid micelles2008

    • Author(s)
      Naoko Yoshida
    • Journal Title

      The Journal of Biochemistry 143(印刷中)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Presentation] 天然型ニューロセルピンのポリマー化機構2010

    • Author(s)
      竹原清日
    • Organizer
      2010年度日本農芸化学会本大会
    • Place of Presentation
      東京大学
    • Year and Date
      2010-03-29
    • Related Report
      2009 Annual Research Report
  • [Presentation] ニューロセルピンのヘリックスF末端はポリマー化を制御する2009

    • Author(s)
      張娟, 竹原清日, 多田俊治, 恩田真紀
    • Organizer
      第82回日本生化学会大会
    • Place of Presentation
      神戸国際会議場
    • Year and Date
      2009-10-22
    • Related Report
      2009 Final Research Report
  • [Presentation] ニューロセルピンのヘリックスF末端はポリマー化を制御する2009

    • Author(s)
      張娟
    • Organizer
      2009年度日本生化学会本大会
    • Place of Presentation
      神戸国際会議場
    • Year and Date
      2009-10-22
    • Related Report
      2009 Annual Research Report
  • [Presentation] ニューロセルピンの結晶構造により明らかとなった複数のポリマー化経路2009

    • Author(s)
      竹原清日
    • Organizer
      2009年度日本生化学会本大会
    • Place of Presentation
      神戸国際会議場
    • Year and Date
      2009-10-22
    • Related Report
      2009 Annual Research Report
  • [Presentation] ニューロセルピンのオメガループ構造と阻害活性制御2009

    • Author(s)
      張娟
    • Organizer
      第9回日本蛋白質科学会年
    • Place of Presentation
      熊本全日空ホテルニュースカイ
    • Year and Date
      2009-05-22
    • Related Report
      2009 Annual Research Report
  • [Presentation] X線結晶構造解析により明らかとなった野生型ニューロセルピンのポリマー化要因2009

    • Author(s)
      竹原清日
    • Organizer
      第9回日本蛋白質科学会年
    • Place of Presentation
      熊本全日空ホテルニュースカイ
    • Year and Date
      2009-05-21
    • Related Report
      2009 Annual Research Report
  • [Presentation] P1-P1' cleaved serpin peptide refolds to the relaxed structure after undergoing a stressed conformation2008

    • Author(s)
      恩田真紀, 竹原清日, 高橋延行, 廣瀬正明
    • Organizer
      The 5th International Symposium on Serpin Biology, Structure and Function
    • Place of Presentation
      ルーベン大学(ベルギー)
    • Year and Date
      2008-07-15
    • Related Report
      2009 Final Research Report
  • [Presentation] P1-P1' cleaved serpin peptide refolds to the relaxed structure after undergoing a stressed conformation2008

    • Author(s)
      Maki Onda
    • Organizer
      The 5th international symposium on serpin biology, structure and function
    • Place of Presentation
      ルーベン大学(ベルギー)
    • Year and Date
      2008-07-15
    • Related Report
      2008 Annual Research Report
  • [Presentation] ニューロセルピンのC末端領域の役割2008

    • Author(s)
      張娟
    • Organizer
      第8回日本蛋白質科学会年
    • Place of Presentation
      タワーホール船堀(東京)
    • Year and Date
      2008-06-12
    • Related Report
      2008 Annual Research Report
  • [Presentation] Cleaved型セルピンは準安定型を経て熱安定型へrefoldする2008

    • Author(s)
      西山 美香
    • Organizer
      日本農芸化学会2008年度大会
    • Place of Presentation
      名城大学
    • Year and Date
      2008-03-27
    • Related Report
      2007 Annual Research Report
  • [Presentation] ニューロセルピンの準安定天然型/熱安定ループ挿入型へのフォールディング2008

    • Author(s)
      竹原 清日
    • Organizer
      日本農芸化学会2008年度大会
    • Place of Presentation
      名城大学
    • Year and Date
      2008-03-27
    • Related Report
      2007 Annual Research Report
  • [Presentation] The Serpin Peptide Fixed on a Column Folds to the Latent Form Avoiding the Native Fold2008

    • Author(s)
      Mika Nishiyama
    • Organizer
      The 5th Open Workshop for Chemistry of Biological Processes Created by Water and Biomolecules
    • Place of Presentation
      奈良県新公会堂
    • Year and Date
      2008-01-25
    • Related Report
      2007 Annual Research Report
  • [Presentation] オボアルブミンの準安定型/熱安定型へのRefolding2007

    • Author(s)
      西山 美香
    • Organizer
      第30回日本分子生物学会年会・第80回日本生化学会大会合同大会
    • Place of Presentation
      パシフィコ横浜
    • Year and Date
      2007-12-14
    • Related Report
      2007 Annual Research Report
  • [Presentation] セルピンのFolding経路2007

    • Author(s)
      恩田 真紀
    • Organizer
      水と生体分子が織り成す生命現象の化学
    • Place of Presentation
      シェラリゾート白馬
    • Year and Date
      2007-08-08
    • Related Report
      2007 Annual Research Report
  • [Presentation] セルピンファミリー蛋白質のポリマー化とコンフォメーション病2007

    • Author(s)
      恩田真紀
    • Organizer
      大阪大学蛋白質研究所セミナー蛋白質の会合と凝集-機能、病気、利用-
    • Place of Presentation
      大阪大学
    • Year and Date
      2007-06-22
    • Related Report
      2009 Final Research Report
  • [Presentation] セルピンファミリー蛋白質のポリマー化とコンフォメーション病2007

    • Author(s)
      恩田 真紀
    • Organizer
      平成19年度大阪大学蛋白質研究所セミナー
    • Place of Presentation
      大阪大学蛋白質研究所
    • Year and Date
      2007-06-22
    • Related Report
      2007 Annual Research Report
  • [Remarks] 本研究課題に関連する総説恩田真紀「解明されたミステリー:セルピン病の発症機構」

    • URL

      http://www.pssj.jp/archives/Art_Lec/Serpin_01/Serpin_01_01.html

    • Related Report
      2009 Final Research Report

URL: 

Published: 2007-04-01   Modified: 2016-04-21  

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