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Structural biology of membrane transporters with a view to drug development

Research Project

Project/Area Number 23000014
Research Category

Grant-in-Aid for Specially Promoted Research

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionThe University of Tokyo

Principal Investigator

TOYOSHIMA Chikashi  東京大学, 分子細胞生物学研究所, 教授 (70172210)

Co-Investigator(Kenkyū-buntansha) OGAWA Haruo  東京大学, 分子細胞生物学研究所, 准教授 (40292726)
MIMURA Hisatoshi  東京大学, 分子細胞生物学研究所, 助教 (30463904)
KANAI Ryuta  東京大学, 分子細胞生物学研究所, 助教 (50598472)
KABASHIMA Yoshiki  東京大学, 分子細胞生物学研究所, 助教 (00580573)
Research Collaborator Inesi Giuseppe  カリフォルニアパシフィック医学センター研究所, 教授
Vilsen Bente  オルフス大学, 教授
Cornelius Flemming  オルフス大学, 教授
Karlish Steven  ワイズマン研究所, 教授
Project Period (FY) 2011 – 2016
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥519,480,000 (Direct Cost: ¥399,600,000、Indirect Cost: ¥119,880,000)
Fiscal Year 2015: ¥89,050,000 (Direct Cost: ¥68,500,000、Indirect Cost: ¥20,550,000)
Fiscal Year 2014: ¥89,050,000 (Direct Cost: ¥68,500,000、Indirect Cost: ¥20,550,000)
Fiscal Year 2013: ¥129,480,000 (Direct Cost: ¥99,600,000、Indirect Cost: ¥29,880,000)
Fiscal Year 2012: ¥105,170,000 (Direct Cost: ¥80,900,000、Indirect Cost: ¥24,270,000)
Fiscal Year 2011: ¥106,730,000 (Direct Cost: ¥82,100,000、Indirect Cost: ¥24,630,000)
Keywordsイオンポンプ / 膜蛋白質 / 結晶解析 / エネルギー変換 / エネルギー交換
Outline of Final Research Achievements

In this project, we aimed at complete understanding of the mechanism of active transport and pursued “why the structures of ion pumps have to be so” by carrying out crystal structure analyses of Ca^<2+>- and Na^+-pumps. With the Ca^<2+>-pump, we succeeded in elucidating the long-awaited E1 crystal structure and showed the regulatory mechanism of sarcolipin, an associated regulatory protein. With the Na^+ pump, we succeeded in determining the crystal structure of a Na^+-bound form for the first time, resulting in the elucidation of an intricate mechanism for selecting Na^+. We also determined the crystal structures of the Na^+-pump with various cardiotonic steroids and thereby opened a way towards developing a tissue specific compound. Furthermore, we succeeded in visualising lipid bilayers in the crystals of Ca^<2+>-ATPase in four states and described detailed interactions with phospholipids.

Assessment Rating
Verification Result (Rating)

A

Assessment Rating
Result (Rating)

A: Progress in the research is steadily towards the initial goal. Expected research results are expected.

Report

(10 results)
  • 2017 Research Progress Assessment (Verification Result) ( PDF )
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Annual Research Report
  • 2014 Annual Research Report   Abstract(Research Progress Assessment) ( PDF )   Research Progress Assessment (Result) ( PDF )
  • 2013 Annual Research Report
  • 2012 Annual Research Report
  • 2011 Annual Research Report
  • Research Products

    (47 results)

All 2017 2016 2015 2014 2013 2011 Other

All Int'l Joint Research (4 results) Journal Article (18 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 18 results,  Open Access: 2 results) Presentation (21 results) (of which Int'l Joint Research: 3 results,  Invited: 13 results) Remarks (4 results)

  • [Int'l Joint Research] Aarhus大学(デンマーク)

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research] Weizmann研究所(イスラエル)

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research] Aarhus大学(デンマーク)

    • Related Report
      2015 Annual Research Report
  • [Int'l Joint Research] Weizmann研究所(イスラエル)

    • Related Report
      2015 Annual Research Report
  • [Journal Article] Protein-lipid interplay revealed with crystals of a Calcium pump2017

    • Author(s)
      Norimatsu, Y and Toyoshima, C
    • Journal Title

      Nature

      Volume: 545 Issue: 7653 Pages: 193-198

    • DOI

      10.1038/nature22357

    • Description
      掲載確定
    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mn^<2+> transport by Ca^<2+>-ATPase of sarcoplasmic reticulum2016

    • Author(s)
      Yonekura, SI and Toyoshima, C
    • Journal Title

      FEBS Letters

      Volume: 590 Issue: 14 Pages: 2086-2095

    • DOI

      10.1002/1873-3468.12244

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The road to understanding an ion pump2016

    • Author(s)
      Toyoshima, C
    • Journal Title

      PHYSICA SCRIPTA

      Volume: 91 Issue: 4 Pages: 042501-042501

    • DOI

      10.1088/0031-8949/91/4/042501

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Functional analysis of SERCA1b, a highly expressed SERCA1 variant in myotonic dystrophy type 1 muscle2015

    • Author(s)
      Zhao, Y., Ogawa, H., Yonekura, S., Mitsuhashi, H., Mitsuhashi, S., Nishino, I., Toyoshima, C., Ishiura, S.
    • Journal Title

      Biochim. Biophys. Acta.

      Volume: 1852 Issue: 10 Pages: 2042-2047

    • DOI

      10.1016/j.bbadis.2015.07.006

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] General and specific lipid-protein interactions in Na, K-ATPase2015

    • Author(s)
      F. Cornelius, M. Habeck, R. Kanai, C. Toyoshima and S. J. D. Karlish
    • Journal Title

      Biochimica et Biophysica Acta-Biomembranes

      Volume: 1848 Issue: 9 Pages: 1729-1743

    • DOI

      10.1016/j.bbamem.2015.03.012

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Sequential substitution of K+ bound to Na+,K+-ATPase visualized by X-ray crystallography2015

    • Author(s)
      Ogawa, H., Cornelius, F., Hirata, A., Toyoshima, C.
    • Journal Title

      Nat Commun.

      Volume: 6 Issue: 1 Pages: 8004-8004

    • DOI

      10.1038/ncomms9004

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Biselyngbyasides, Cytotoxic Marine Macrolides, are Novel and Potent Inhibitors of the Ca2+ Pumps with a Unique Mode of Binding2015

    • Author(s)
      Morita, M., Ogawa, H., Ohno, O., Yamori, T., Suenaga, K., Toyoshima, C.
    • Journal Title

      FEBS Lett.

      Volume: 589 Issue: 13 Pages: 1406-1411

    • DOI

      10.1016/j.febslet.2015.04.056

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Biselyngbyasides, cytotoxic marine macrolides, are novel and potent inhibitors of the Ca^<2+>pumps with a unique mode of binding2015

    • Author(s)
      M. Morita, H. Ogawa, 0. Ohno, T. Yamori, K. Suenaga, C. Toyoshima
    • Journal Title

      FEBS Letters

    • Description
      【掲載確定】 印刷中
    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Electron crystallography of ultrathin 3D protein crystals : Atomic models with charges2015

    • Author(s)
      K. Yonekura, K. Kato, M. Ogasawara, M. Tomita and C. Toyoshima
    • Journal Title

      Proc. Nat. Acad. Sci. USA

      Volume: 112 Issue: 11 Pages: 3368-3373

    • DOI

      10.1073/pnas.1500724112

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Stimulation, inhibition or stabilization of Na, K-ATPase caused by specific lipid interactions at distinct sites2015

    • Author(s)
      M. Habeck, H. Haviv, A. Katz, E. Kapri-Pardes, S. Ayciriex, A. Shevchenko, H. Ogawa, C. Toyoshima, and S.J.D. Karlish
    • Journal Title

      J. Biol. Chem.

      Volume: 290 Issue: 8 Pages: 4829-4842

    • DOI

      10.1074/jbc.m114.611384

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] ATPase-dependent auto-phosphorylation of the open condensin hinge diminishes DNA binding2014

    • Author(s)
      Y. Akai, R. Kanai, N. Nakazawa, M. Ebe, C. Toyoshima and M. Yanagida
    • Journal Title

      Open Biol.

      Volume: 4 Issue: 12 Pages: 140193-140193

    • DOI

      10.1098/rsob.140193

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Crystal structure of a Na^+-bound Na^+, K^+-ATPase preceding the E1P state.2013

    • Author(s)
      R. Kanai, H. Ogawa, B. Vilsen, F. Cornelius and C. Toyoshima
    • Journal Title

      Nature

      Volume: 502 Issue: 7470 Pages: 201-206

    • DOI

      10.1038/nature12578

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] New crystal structures of PII-type ATPases : Excitement continues.2013

    • Author(s)
      C. Toyoshima and F. Cornelius
    • Journal Title

      Curr. Opinion Struct. Biol.

      Volume: 23 Issue: 4 Pages: 507-514

    • DOI

      10.1016/j.sbi.2013.06.005

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Crystal structures of the calcium pump and sarcolipin in the E1·Mg2+ state.2013

    • Author(s)
      C. Toyoshima
    • Journal Title

      Nature

      Volume: 495 Issue: 7440 Pages: 260-264

    • DOI

      10.1038/nature11899

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Neutral phospholipids stimulate Na,K-ATPase activity: a specific lipid-protein interaction2013

    • Author(s)
      H. Haviv
    • Journal Title

      J. Biol. Chem.

      Volume: 288 Issue: 14 Pages: 10073-10081

    • DOI

      10.1074/jbc.m112.446997

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A structural view on the functional importance of the sugar moiety and steroid hydroxyls of cardiotonic steroids in binding to Na,K-ATPase.2013

    • Author(s)
      F. Cornelius
    • Journal Title

      J. Biol. Chem.

      Volume: 288 Pages: 6602-6616

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] First crystal structures of Na^+, K^+-ATPase : New light on the oldest ion pump2011

    • Author(s)
      C.Toyoshima, et al.
    • Journal Title

      Structure

      Volume: 19 Issue: 12 Pages: 1732-1738

    • DOI

      10.1016/j.str.2011.10.016

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Metal fluoride Complexes of Na, K-ATPase2011

    • Author(s)
      F.Cornelius, et al.
    • Journal Title

      J.Biol.Chem.

      Volume: 286 Pages: 29882-29892

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Presentation] カルシウムポンプの構造生物学 - 燐脂質との相互作用2017

    • Author(s)
      豊島 近
    • Organizer
      第2回生物構造学研究会
    • Place of Presentation
      研究社英語センター大会議室(東京都新宿区)
    • Year and Date
      2017-03-29
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Protein-Lipid Interplay as Revealed by X-ray Solvent Contrast Modulation with the crystals of Ca^<2+>-ATPases in four different States2017

    • Author(s)
      豊島 近
    • Organizer
      IGER International Symposium on Physics of Life
    • Place of Presentation
      名古屋大学(愛知県名古屋市)
    • Year and Date
      2017-03-26
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Large-scale production of mammalian membrane proteins toward determination of high resolution structures2017

    • Author(s)
      Haruo Ogawa, Chikashi Toyoshima
    • Organizer
      Biophysical Society 61st Annual Meeting
    • Place of Presentation
      Ernest N. Morial Convention Center(米国ニューオーリンズ)
    • Year and Date
      2017-02-13
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Ca2+-ポンプ構造研究の最前線2016

    • Author(s)
      小川治夫、椛島佳樹、豊島近
    • Organizer
      日本生体エネルギー研究会第42回討論会
    • Place of Presentation
      名古屋工業大学4号館ホール(愛知県名古屋市)
    • Year and Date
      2016-12-20
    • Related Report
      2016 Annual Research Report
  • [Presentation] 高分解能構造解析へ向けた哺乳類由来膜蛋白質の大量生産2016

    • Author(s)
      小川治夫、村山尚、呉林なごみ、豊島近
    • Organizer
      第89回 日本生化学会大会シンポジウム
    • Place of Presentation
      仙台国際センター(宮城県仙台市)
    • Year and Date
      2016-09-26
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Stuructural biology of P-type ion translocating ATPases : towards complete understanding of the mechanism2016

    • Author(s)
      C. Toyoshima
    • Organizer
      Aminoff Prize Symposium2016
    • Place of Presentation
      University of Gothenburg (Gothenburg, Sweden)
    • Year and Date
      2016-03-30
    • Description
      【発行確定】
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] X線結晶構造解析によるキネティックス測定 : Na^+, K^+-ATPaseに結合したK^+は段階的に置換される2015

    • Author(s)
      小川 治夫
    • Organizer
      日本生体エネルギー研究会 第41回討論会
    • Place of Presentation
      東京大学(東京都文京区)
    • Year and Date
      2015-12-22
    • Description
      【発表確定】
    • Related Report
      2015 Annual Research Report
  • [Presentation] Kinetics by X-ray crystallography : sequential substitution of K^+ bound to Na^+, K^+-ATPase2015

    • Author(s)
      H. Ogawa, A. Hirata, F. Cornelius, C. Toyoshima
    • Organizer
      第38回日本分子生物学会 第88回日本生化学会合同大会(ワークショップオーガナイザー)
    • Place of Presentation
      神戸ポートアイランド(兵庫県神戸市)
    • Year and Date
      2015-12-02
    • Description
      【発表確定】
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] Sequential substitution of bound K^+ in the transmembrane binding sites of Na^+, K^+-ATPase : Kinetics by X-ray crystallography2015

    • Author(s)
      H. Ogawa, A. Hirata, F. Cornelius, C. Toyoshima
    • Organizer
      日本生物物理学会第53回年会シンポジウム「輸送膜タンパク質のダイナミクス」
    • Place of Presentation
      金沢大学(石川県金沢市)
    • Year and Date
      2015-09-15
    • Description
      【発行確定】
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] イオンポンプ蛋白質の構造生物学とSPring-82015

    • Author(s)
      豊島 近
    • Organizer
      SPring-8シンポジウム2015
    • Place of Presentation
      九州大学(福岡市)
    • Year and Date
      2015-09-13
    • Description
      【発行確定】
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] How Na^+, K^+-ATPase select andpumps sodium across the membrane, Visualization of lipid bilayers in the crystals of calcium pump2015

    • Author(s)
      C. Toyoshima
    • Organizer
      2nd NTU Membrane Protein Weeks
    • Place of Presentation
      台湾大学台北市, 台湾
    • Year and Date
      2015-03-23 – 2015-03-25
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] X-ray crystallographic study of Na, K-ATPase in complex with cardiotonic steroids2015

    • Author(s)
      H. Ogawa, et al.
    • Organizer
      Biophysical Society 59th Annual Meeting
    • Place of Presentation
      Baltimore Convension Center Baltimore, アメリカ
    • Year and Date
      2015-02-09
    • Related Report
      2014 Annual Research Report
  • [Presentation] New crystal structures of Ca^<2+>-ATPase(SERCA) and Na^+, K^+-ATPases2014

    • Author(s)
      C. Toyoshima
    • Organizer
      Barcelona BioMed Conference, Transporters and other molecular machines
    • Place of Presentation
      the Sala Prat de Riba バルセロナ, スペイン
    • Year and Date
      2014-11-18
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Na^+, K^+-ATPaseと強心配糖体複合体のX線結晶構造解析2014

    • Author(s)
      小川治夫
    • Organizer
      第87回日本生化学会大会
    • Place of Presentation
      国立京都国際会館(京都府京都市)
    • Year and Date
      2014-10-17
    • Related Report
      2014 Annual Research Report
  • [Presentation] New crystal structures of Ca^<2+>-and Na^+, K^+-ATPases2014

    • Author(s)
      C. Toyoshima
    • Organizer
      ASBMB Special Symposia Series, Na, K-ATPase and Related Transport ATPases
    • Place of Presentation
      De Werelt Conference Centre, Lunteren, オランダ
    • Year and Date
      2014-09-01
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] イオンポンプの構造生物学 : 全ての反射点の利用2013

    • Author(s)
      豊島 近
    • Organizer
      第13回日本蛋白質科学会年会
    • Place of Presentation
      とりぎん文化会館(鳥取市)
    • Year and Date
      2013-06-14
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Structural Understanding of ion Pumping by P-type ATPases.2013

    • Author(s)
      C. Toyoshima
    • Organizer
      Benzon Symposium No. 59
    • Place of Presentation
      Hotel Skt. Petriコペンハーゲンデンマーク
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Sequential Substitution of Bound K^+ in the Transmembrane Binding Sites of Na^+, K^+-ATPase2011

    • Author(s)
      H.Ogawa
    • Organizer
      13TH INTERNATIONAL ATPase CONFERENCE Na, K-ATPase AND RELATED ATPases
    • Place of Presentation
      Pacific Grove, CA, USA
    • Year and Date
      2011-09-28
    • Related Report
      2011 Annual Research Report
  • [Presentation] カルシウムATPaseの作動機構の理解と結晶構造解析2011

    • Author(s)
      豊島近
    • Organizer
      第84回日本生化学会大会
    • Place of Presentation
      京都(招待講演)
    • Year and Date
      2011-09-22
    • Related Report
      2011 Annual Research Report
  • [Presentation] Do lipid bilayers follow movements of transmembrane helices? If so, to what extent?2011

    • Author(s)
      C.Toyoshima
    • Organizer
      The EMBO Meeting 2011
    • Place of Presentation
      Vienna, Austria(招待講演)
    • Year and Date
      2011-09-12
    • Related Report
      2011 Annual Research Report
  • [Presentation] Structural study on the calcium ATPase: ion pumping mechanism and its regulation

    • Author(s)
      C. Toyoshima
    • Organizer
      The 1st NRPB International Symposium and Workshop for Membrane Proteins
    • Place of Presentation
      Academia Sinica, Taipei, Taiwan
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Remarks] 東京大学分子細胞生物学研究所膜蛋白質解析研究分野ホームページ

    • URL

      http://www.iam.u-tokyo.ac.jp/StrBiol/index.html

    • Related Report
      2016 Annual Research Report 2015 Annual Research Report
  • [Remarks]

    • URL

      http://www.iam.u-tokyo.ac.jp/StrBiol/index.html

    • Related Report
      2014 Annual Research Report
  • [Remarks]

    • URL

      http://www.iam.u-tokyo.ac.jp/StrBiol/index.html

    • Related Report
      2013 Annual Research Report
  • [Remarks]

    • URL

      http://www.iam.u-tokyo.ac.jp/StrBiol/index.html

    • Related Report
      2011 Annual Research Report

URL: 

Published: 2011-06-18   Modified: 2022-11-04  

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