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Elucidation of the molecular valve in the transporter to determine the direction of the transporter cycle

Research Project

Project/Area Number 26460044
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Physical pharmacy
Research InstitutionToho University

Principal Investigator

MIYAUCHI Seiji  東邦大学, 薬学部, 教授 (30202352)

Co-Investigator(Kenkyū-buntansha) 菊川 峰志  北海道大学, 先端生命科学研究院, 講師 (20281842)
Project Period (FY) 2014-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywordsトランスポーター / 分子弁 / 水素結合ネットワーク / 輸送サイクル / 基質認識機構 / モジュレーター / 起電性輸送担体
Outline of Final Research Achievements

To elucidate how the molecular valve can determine the direction of the transporter cycle in the transporter accompanying ion movement, we precisely determined the transports of human oligopeptide transporter (hPEPT1) and human Na+/monocarboxylate co-transporter (hSMCT1).
(1) We demonstrated using a chemical modification reagent for hydroxyl group, phenylmethylsulfonylfluoride (PMSF) that the hydroxyl group of Ser302 weakly forms the hydrogen-bonding with the imidazole of His57, which might keep the uptake activity optimum in the range of physiological intestinal pH.
(2) We elucidated with quantitative activity-structure relationship (QASR) that the molecular valve hSMCT1 might also determine the transport-direction of coupling Na+ ion and substrate.

Report

(4 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Research-status Report
  • 2014 Research-status Report
  • Research Products

    (29 results)

All 2017 2016 2015 2014

All Journal Article (5 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 5 results,  Open Access: 3 results,  Acknowledgement Compliant: 2 results) Presentation (24 results) (of which Int'l Joint Research: 2 results,  Invited: 3 results)

  • [Journal Article] X-ray crystallographic structure of thermophilic rhodopsin: implications for high thermal stability and optogenetic function2016

    • Author(s)
      Tsukamoto T, Mizutani K, Hasegawa T, Takahashi M, Honda N, Hashimoto N, Shimono K, Yamashita K, Yamamoto M, Miyauchi S, Takagi S, Hayashi S, Murata T, Sudo Y.
    • Journal Title

      J. Biol. Chem.

      Volume: in press Issue: 23 Pages: 12223-12232

    • DOI

      10.1074/jbc.m116.719815

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Formation of M-Like Intermediates in Proteorhodopsin in Alkali Solutions (pH less than 8.5) Where the Proton Release Occurs First in Contrast to the Sequence at Lower pH2016

    • Author(s)
      Tamogami J, Sato K, Kurokawa S, Yamada T, Nara T, Demura M, Miyauchi S, Kikukawa T, Muneyuki E, Kamo N
    • Journal Title

      Biochemistry

      Volume: 55 Issue: 7 Pages: 1036-1048

    • DOI

      10.1021/acs.biochem.5b01196

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Structural basis for the slow photocycle and late proton release in Acetabularia rhodopsin I from the marine plant Acetabularia acetabulum2015

    • Author(s)
      Furuse M, Tamogami J, Hosaka T, Kikukawa T, Shinya N, Hato M, Ohsawa N, Kim SY, Jung KH, Demura M, Miyauchi S, Kamo N, Shimono K,Kimura-Someya T, Yokoyama S, Shirouzu M
    • Journal Title

      Acta Crystallogr D Biol Crystallogr

      Volume: 71 Issue: 11 Pages: 2203-2216

    • DOI

      10.1107/s1399004715015722

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Converting a light-driven proton pump into a light-gated proton channel2015

    • Author(s)
      K. Inoue, T. Tsukamoto, K. Shimono, Y. Suzuki, S. Miyauchi, S. Hayashi, H. Kandori, Y. Sudo*
    • Journal Title

      J. Am. Chem. Soc.

      Volume: 137 Issue: 9 Pages: 3291-3299

    • DOI

      10.1021/ja511788f

    • Related Report
      2014 Research-status Report
    • Peer Reviewed
  • [Journal Article] Electrophysiological characterization of human Na+/taurocholate cotransporting polypeptide (hNTCP) heterologously expressed in Xenopus laevis oocytes2014

    • Author(s)
      Masuda M, Ichikawa Y, Shimono K, Shimizu M, Tanaka Y, Nara T, Miyauchi S
    • Journal Title

      Arch Biochem Biophys

      Volume: 562 Pages: 115-121

    • DOI

      10.1016/j.abb.2014.08.010

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Presentation] Effect of albumin on the hepatic uptake/pharmacokinetics of highly bound drug2017

    • Author(s)
      Seiji Miyauchi
    • Organizer
      THE 9th SUGIYAMA LABORATORY (RIKEN) OPEN SYMPOSIUM
    • Place of Presentation
      RIKEN Yokohama Main Building Hall (Yokohama, Kanagawa)
    • Year and Date
      2017-02-24
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 熱力学的測定によるオリゴペプチド輸送担体(YdgR)の基質認識 における多選択機構の解析2016

    • Author(s)
      下野和実、大森明子、宮内正二
    • Organizer
      第38回生体膜と薬物の相互作用シンポジウム
    • Place of Presentation
      名古屋市立大学大学院薬学研究科・図書館棟(愛知県、名古屋市)
    • Year and Date
      2016-11-17
    • Related Report
      2016 Annual Research Report
  • [Presentation] Na+-coupled monocarboxylate transporter SMCT1 (SLC5A8) has versatile ability to transport cyclic amino acid derivates in the form of zwitterions2016

    • Author(s)
      Seiji Miyauchi, Kazuaki Sugio, Masayuki Masuda, Kazumi Shimono, Vadivel Ganapathy
    • Organizer
      2016 American Association of Pharmaceutical Scientists Annual Meeting and Exposition
    • Place of Presentation
      Colorado Convention Center (Denver, CO (USA))
    • Year and Date
      2016-11-15
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 多剤輸送担体EmrEの基質結合エントロピー利得に対する水分子の寄与2016

    • Author(s)
      下野 和実、松田 佳祐、鈴木 翔子、矢嶋 香歩、山本 祥世、染谷 友美、白水 美香子、横山 茂之、宮内 正二
    • Organizer
      第54回日本生物物理学会年会
    • Place of Presentation
      つくば国際会議場(茨城県、つくば市)
    • Year and Date
      2016-09-27
    • Related Report
      2016 Annual Research Report
  • [Presentation] サーモフィリックロドプシンの耐熱性・高光遺伝学活性の構造基盤2016

    • Author(s)
      塚本 卓、水谷 健二、長谷川 太祐、高橋 めぐみ、本田 尚也、橋本 直記、下野 和実、宮内 正二、高木 新、林 重彦、村田 武士、須藤 雄気
    • Organizer
      第54回日本生物物理学会年会
    • Place of Presentation
      つくば国際会議場(茨城県、つくば市)
    • Year and Date
      2016-09-26
    • Related Report
      2016 Annual Research Report
  • [Presentation] アセタブラリアロドプシンIIのプロトン移動におけるD92およびC218残基間の相互作用の役割2016

    • Author(s)
      田母神 淳、菊川 峰志、 大川 啓介、大沢 登、伊達 公平、奈良 敏文、出村 誠、染谷 友美、白水 美香子、横山 茂之、宮内 正二、下野 和実、加茂 直樹
    • Organizer
      第54回日本生物物理学会年会
    • Place of Presentation
      つくば国際会議場(茨城県、つくば市)
    • Year and Date
      2016-09-25
    • Related Report
      2016 Annual Research Report
  • [Presentation] 大腸菌 H + /オリゴペプチド共輸送担体(YdgR)における多選択的基質認識機構の熱力学的解析2016

    • Author(s)
      大森明子、下野和実、宮内正二
    • Organizer
      第11回トランスポーター研究会年会
    • Place of Presentation
      京都大学・宇治キャンパスきはだホール(京都府、宇治市)
    • Year and Date
      2016-07-02
    • Related Report
      2016 Annual Research Report
  • [Presentation] ヒト Na+ /モノカルボン酸共輸送担体(SMCT1)の多彩な基質輸送能力2016

    • Author(s)
      杉尾和昭、猪田大誠、鴇田翔平、増田雅行、下野和実、宮内正二
    • Organizer
      第11回トランスポーター研究会年会
    • Place of Presentation
      京都大学・宇治キャンパスきはだホール(京都府、宇治市)
    • Year and Date
      2016-07-02
    • Related Report
      2016 Annual Research Report
  • [Presentation] 血清アルブミン肝取り込み促進機構モデルの構築2016

    • Author(s)
      花島絵里加、増田雅行、下野和実、杉山雄一、宮内正二
    • Organizer
      日本薬剤学会第31年会
    • Place of Presentation
      長良川国際会議場(岐阜県、岐阜市)
    • Year and Date
      2016-05-19
    • Related Report
      2016 Annual Research Report
  • [Presentation] ヒト肝癌由来HepG2細胞におけるNa+/オリゴペプチド共輸送担体の機能解析2016

    • Author(s)
      小林朱音、國貞直人、下野和実、宮内正二
    • Organizer
      日本薬剤学会第31年会
    • Place of Presentation
      長良川国際会議場(岐阜県、岐阜市)
    • Year and Date
      2016-05-19
    • Related Report
      2016 Annual Research Report
  • [Presentation] Na+/モノカルボン酸共輸送担体(SMCT1)の多彩な基質輸送能力2016

    • Author(s)
      杉尾和昭、猪田大誠、増田雅行、下野和実、真坂亙、宮内正二
    • Organizer
      日本薬剤学会第31年会
    • Place of Presentation
      長良川国際会議場(岐阜県、岐阜市)
    • Year and Date
      2016-05-19
    • Related Report
      2016 Annual Research Report
  • [Presentation] Can "free drug theory" feasibly evaluate the hepatic uptake clearance of a drug with highly protein binding?2016

    • Author(s)
      Seiji Miyauchi
    • Organizer
      THE 7th SUGIYAMA LABORATORY (RIKEN) OPEN SYMPOSIUM
    • Place of Presentation
      RIKEN Yokohama Main Building Hall (Yokohama, Kanagawa)
    • Year and Date
      2016-02-16
    • Related Report
      2015 Research-status Report
    • Invited
  • [Presentation] Na+モノカルボン酸輸送担体(SMCT)の有する多様な基質認識能力2015

    • Author(s)
      杉尾和昭、猪田大誠、鴇田翔平、増田雅行、下野和実、宮内正二
    • Organizer
      第37回生体膜と薬物の相互作用シンポジウム
    • Place of Presentation
      熊本大学薬学部・研究総合棟(熊本県、熊本市)
    • Year and Date
      2015-11-20
    • Related Report
      2015 Research-status Report
  • [Presentation] A novel hepatic transport model considering a significant ligand-transporter binding leading to a change in unbound fraction in the medium, which can feasibly explain the “albumin-mediated hepatic uptake” phonomenon2015

    • Author(s)
      Seiji Miyauchi, Masayuki Masuda, Yuudai Tanaka, Shouko Iwakado, Kazumi Shimono, SooJin Kim, Yuichi Sugiyama
    • Organizer
      30th Japanese Society for the Study of Xenobiotics Annual Meeting
    • Place of Presentation
      Tower Hall Funabori (Edogawa, Tokyo)
    • Year and Date
      2015-11-14
    • Related Report
      2015 Research-status Report
  • [Presentation] Involvement of human Na+/taurocholate (TCA) cotransporting polypeptide (hNTCP) in the hepatic uptake of various statins2015

    • Author(s)
      Masayuki Masuda, Kazuaki Sugio, Kazumi Shimono, Seiji Miyauchi
    • Organizer
      2015 American Association of Pharmaceutical Scientists Annual Meeting and Exposition
    • Place of Presentation
      Orange County Convention Center (Orlando, FLA, USA)
    • Year and Date
      2015-10-28
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] 血清アルブミンの有機アニオンの肝取り込みに及ぼす影響2015

    • Author(s)
      増田雅行、田中裕大、岩角祥子、下野和実、真坂亙、宮内正二
    • Organizer
      日本薬剤学会第30年会
    • Place of Presentation
      長崎ブリックホール(長崎県、長崎市)
    • Year and Date
      2015-05-21
    • Related Report
      2015 Research-status Report
  • [Presentation] Na+/モノカルボン酸輸送担体におけるブロードな基質認識機構の解明2015

    • Author(s)
      杉尾和昭、猪田大誠、増田雅行、下野和実、真坂 亙、宮内正二
    • Organizer
      日本薬剤学会第30年会
    • Place of Presentation
      長崎ブリックホール(長崎県、長崎市)
    • Year and Date
      2015-05-21
    • Related Report
      2015 Research-status Report
  • [Presentation] Na+/モノカルボン酸共輸送担体(SMCT)におけるブロードな基質認識機構の解明2015

    • Author(s)
      猪田大誠、鴇田翔平、増田雅行、杉尾和昭、清水真紀、奈良敏文、下野和実、宮内正二
    • Organizer
      日本薬学会第135回年会
    • Place of Presentation
      神戸サンボーホール (兵庫県、神戸市)
    • Year and Date
      2015-03-26
    • Related Report
      2014 Research-status Report
  • [Presentation] 電気生理学的手法を用いた起電性薬物輸送担体の基質認識機構の解明2015

    • Author(s)
      宮内正二
    • Organizer
      第5回杉山特別研究室(理研)公開シンポジウム
    • Place of Presentation
      理化学研究所横浜事業交流棟ホール (神奈川県、横浜市)
    • Year and Date
      2015-02-10
    • Related Report
      2014 Research-status Report
    • Invited
  • [Presentation] 血清アルブミンによる蛍光試薬ANS肝取り込み促進機構の解明2014

    • Author(s)
      田中裕大、増田雅行、岩角祥子、下野和実、奈良敏文、宮内正二
    • Organizer
      第36回生体膜と薬物の相互作用シンポジウム
    • Place of Presentation
      徳島大学藤井節郎記念ホール・大塚講堂 (徳島県、徳島市)
    • Year and Date
      2014-11-20
    • Related Report
      2014 Research-status Report
  • [Presentation] Involvement of a new pH-dependent transporter in the uptake of 2, 4-dichloro phenoxyacetate (2,4-D) by primary cultured rat hepatocytes2014

    • Author(s)
      Seiji Miyauchi, Hiroki Ohno, Masayuki Masuda, Toshifumi Nara, Kazumi Shimono
    • Organizer
      2014 American Association of Pharmaceutical Scientists Annual Meeting and Exposition
    • Place of Presentation
      San Diego Convention Center (San Diego, CA, USA)
    • Year and Date
      2014-11-06
    • Related Report
      2014 Research-status Report
  • [Presentation] Albumin mediated uptake of 1-anilino 8-naphthalene sulfonate (ANS) by primary cultured rat hepatocytes2014

    • Author(s)
      Seiji Miyauchi, Yuudai Tanaka, Masayuki Masuda, Toshifumi Nara, Kazumi Shimono
    • Organizer
      29th Japanese/19th International Society for the Study of Xenobiotics Joint Meeting
    • Place of Presentation
      San Francisco Union Square Hilton (San Francisco, CA, USA)
    • Year and Date
      2014-10-22
    • Related Report
      2014 Research-status Report
  • [Presentation] 血清アルブミンの蛍光試薬ANSの肝取り込み及ぼす影響2014

    • Author(s)
      田中裕大、下野和実、宮内正二
    • Organizer
      第29回日本薬剤学会年会
    • Place of Presentation
      大宮ソニックシティビル(埼玉県、さいたま市)
    • Year and Date
      2014-05-22
    • Related Report
      2014 Research-status Report
  • [Presentation] 2,4-dichloro phenoxyacetate (2,4-D) の肝取り込み機構の解明2014

    • Author(s)
      宮内正二、大野裕樹、下野和実
    • Organizer
      第29回日本薬剤学会年会
    • Place of Presentation
      大宮ソニックシティビル(埼玉県、さいたま市)
    • Year and Date
      2014-05-22
    • Related Report
      2014 Research-status Report

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Published: 2014-04-04   Modified: 2018-03-22  

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