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Structural elucidation of the mechanism underlying biased signaling of GPCRs

Research Project

Project/Area Number 25460033
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Physical pharmacy
Research InstitutionThe University of Tokyo

Principal Investigator

Ueda Takumi  東京大学, 薬学研究科(研究院), 助教 (20451859)

Co-Investigator(Kenkyū-buntansha) Ichio Shimada  東京大学, 大学院薬学系研究科, 教授 (70196476)
Project Period (FY) 2013-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
KeywordsGPCR / NMR / 膜タンパク質 / 構造生物学 / 膜蛋白質 / 蛋白質 / 薬学 / シグナル伝達
Outline of Final Research Achievements

To increase the signal intensities, a deuteration method was developed for GPCRs expressed in an insect cell/baculovirus expression system. The NMR sensitivities of the methionine methyl resonances from the β2-adrenergic receptor (β2AR) in lipid bilayers of reconstituted high-density lipoprotein (rHDL) increased by approximately 5-fold upon deuteration. NMR analyses revealed that the exchange rates for the conformational equilibrium of β2AR in rHDLs were remarkably different from those measured in detergents. The timescales of GPCR signaling, calculated from the exchange rates, are faster than those of receptor tyrosine kinases and thus enable rapid neurotransmission and sensory perception. We could also identified conformational equilibrium of GPCRs that determine their biased signaling.

Report

(4 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Research-status Report
  • 2013 Research-status Report
  • Research Products

    (14 results)

All 2016 2015 2014 2013 Other

All Journal Article (7 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 7 results,  Open Access: 5 results,  Acknowledgement Compliant: 4 results) Presentation (6 results) (of which Invited: 4 results) Remarks (1 results)

  • [Journal Article] Conductance of P2X4 receptor is determined by conformational equilibrium in the transmembrane region2016

    • Author(s)
      Minato Y, Suzuki S , Hara T, Kofuku Y, Kasuya G, Fujiwara Y, Igarashi S, Suzuki E, Nureki O, Hattori M, Ueda T, Shimada I
    • Journal Title

      Proc. Natl. Acad. Sci.

      Volume: 発行中 Issue: 17 Pages: 4741-4746

    • DOI

      10.1073/pnas.1600519113

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Elucidation of the CCR1- and CCR5-binding modes of MIP-1α by application of an NMR spectra reconstruction method to the transferred cross-saturation experiments.2015

    • Author(s)
      Chie Yoshiura, Takumi Ueda, Yutaka Kofuku, Masahiko Matsumoto, Junya Okude, Keita Kondo, Yutaro Shiraishi, Ichio Shimada
    • Journal Title

      Journal of Biomolecular NMR

      Volume: 63 Issue: 4 Pages: 333-340

    • DOI

      10.1007/s10858-015-9992-x

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of a Conformational Equilibrium That Determines the Efficacy and Functional Selectivity of the μ-Opioid Receptor.2015

    • Author(s)
      Junya Okude, Takumi Ueda, Yutaka Kofuku, Motohiko Sato, Naoyuki Nobuyama, Keita Kondo, Yutaro Shiraishi, Takuya Mizumura, Kento Onishi, Mei Natsume, Masahiro Maeda, Hideki Tsujishita, Takefumi Kuranaga, Masayuki Inoue, Ichio Shimada
    • Journal Title

      Angewandte Chemie International Edition

      Volume: 21 Issue: 52 Pages: 15771-15776

    • DOI

      10.1002/anie.201508794

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development of a method for reconstruction of crowded NMR spectra from undersampled time-domain data2015

    • Author(s)
      Ueda T, Yoshiura C, Matsumoto M, Kofuku Y, Okude J, Kondo K, Shiraishi Y, Takeuchi K, Shimada I
    • Journal Title

      J. Biomol. NMR

      Volume: 印刷中 Issue: 1 Pages: 31-41

    • DOI

      10.1007/s10858-015-9908-9

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Functional dynamics of deuterated β2 -adrenergic receptor in lipid bilayers revealed by NMR spectroscopy2014

    • Author(s)
      Kofuku Y, Ueda T, Okude J, Shiraishi Y, Kondo K, Mizumura T, Suzuki S, Shimada I
    • Journal Title

      Angew Chem Int Ed Engl

      Volume: 53 Issue: 49 Pages: 13376-13379

    • DOI

      10.1002/anie.201406603

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Functional dynamics of cell surface membrane proteins2014

    • Author(s)
      Nishida N, Osawa M, Takeuchi K, Imai S, Stampoulis P, Kofuku Y, Ueda T, Shimada I
    • Journal Title

      J Magn Reson

      Volume: 241 Pages: 86-96

    • DOI

      10.1016/j.jmr.2013.11.007

    • Related Report
      2013 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Cross-saturation and transferred cross-saturation experiments2014

    • Author(s)
      Ueda T, Takeuchi K, Nishida N, Stampoulis P, Kofuku Y, Osawa M, Shimada I
    • Journal Title

      Q Rev Biophys

      Volume: 47 Issue: 2 Pages: 143-187

    • DOI

      10.1017/s0033583514000043

    • Related Report
      2013 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Presentation] 多次元NMRスペクトル再構成法の開発とケモカイン-ケモカイン受容体複合体の転移交差飽和実験への応用2015

    • Author(s)
      上田卓見, 吉浦知絵, 幸福裕, 松本昌彦, 奥出順也, 近藤啓太, 白石勇太郎, 嶋田一夫
    • Organizer
      第54回NMR討論会
    • Place of Presentation
      千葉工業大学津田沼キャンパス、千葉
    • Year and Date
      2015-11-08
    • Related Report
      2015 Annual Research Report
  • [Presentation] リガンドとの相互作用に伴う膜蛋白質の 動的立体構造変化2015

    • Author(s)
      上田卓見、幸福裕、嶋田一夫
    • Organizer
      第53回生物物理学会
    • Place of Presentation
      金沢大学角間キャンパス、金沢
    • Year and Date
      2015-09-14
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] NMRによる、限定されたデータからのGPCRの動的構造情報の抽出2014

    • Author(s)
      上田 卓見
    • Organizer
      第14回蛋白質科学会年会
    • Place of Presentation
      横浜
    • Year and Date
      2014-06-25 – 2014-06-27
    • Related Report
      2014 Research-status Report
    • Invited
  • [Presentation] NMRを用いた過渡的蛋白質-蛋白質複合体の結合様式の解明2014

    • Author(s)
      上田卓見
    • Organizer
      大阪大学蛋白質研究所セミナー "結晶構造を併用したハイブリッド構造研究の最前線"
    • Place of Presentation
      大阪府・大阪大学蛋白質研究所
    • Related Report
      2013 Research-status Report
    • Invited
  • [Presentation] 二次点NMRインターフェログラム再構成法の開発およびCCR5のMIP-1α結合様式の解明への応用2014

    • Author(s)
      上田卓見、吉浦知絵、松本昌彦、幸福裕、奥出順也、近藤啓太、白石勇太郎、嶋田一夫
    • Organizer
      日本薬学会第134年会
    • Place of Presentation
      熊本県・熊本市総合体育館
    • Related Report
      2013 Research-status Report
  • [Presentation] NMRによるGタンパク質共役型受容体の機能解明2013

    • Author(s)
      上田 卓見
    • Organizer
      第4回 神経科学と構造生物学の融合研究会
    • Place of Presentation
      愛知県・岡崎コンファレンスセンター
    • Related Report
      2013 Research-status Report
    • Invited
  • [Remarks]

    • Related Report
      2014 Research-status Report

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Published: 2014-07-25   Modified: 2019-07-29  

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