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Crystallographic study of the mammalian bile acid transporter NTCP in complex with its conformation-specific antibodies

Research Project

Project/Area Number 15K06968
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Structural biochemistry
Research InstitutionKyoto University

Principal Investigator

Nomura Norimichi  京都大学, 医学研究科, 助教 (10314246)

Co-Investigator(Renkei-kenkyūsha) IWATA So  京都大学, 大学院医学研究科, 教授 (60452330)
SHIMAMURA Tatsuro  京都大学, 大学院医学研究科, 特定講師 (90391979)
Project Period (FY) 2015-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords膜タンパク質 / 抗体 / X線結晶構造解析 / 創薬ターゲット / 高脂血症 / 胆汁酸 / トランスポーター / コレステロール / 膜蛋白質
Outline of Final Research Achievements

High cholesterol levels greatly increase the risk of cardiovascular disease. By its conversion into bile acids, about 50% of cholesterol is eliminated from the body. However bile acids released from the bile duct are constantly recycled, being reabsorbed in the intestine via sodium dependent bile acid transporters. ASBT and NTCP, both of which are SLC10 (Sodium bile acid co-transporter family) members, have received attention as a new target of therapeutic drugs. In this study, our efforts have been devoted to crystallization of the mammalian NTCP in complex with its conformation-specific antibody fragments.
A number of NTCP mutants that show high thermostability and monodispersity on size-exclusion chromatography (SEC) have been isolated. In addition, a total of six clones of antibodies that specifically recognize confomational epitope on the NTCP have been developed. Crystallization screening of the NTCP mutant-Fab complex is currently underway.

Report

(4 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Research-status Report
  • 2015 Research-status Report
  • Research Products

    (13 results)

All 2018 2017 2016 2015 Other

All Int'l Joint Research (3 results) Journal Article (6 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 5 results,  Open Access: 3 results,  Acknowledgement Compliant: 3 results) Book (2 results) Remarks (2 results)

  • [Int'l Joint Research] ストックホルム大学(スウェーデン)

    • Related Report
      2016 Research-status Report
  • [Int'l Joint Research] ストックホルム大学(スウェーデン)

    • Related Report
      2015 Research-status Report
  • [Int'l Joint Research] インペリアルカレッジロンドン/ダイアモンド放射光施設(英国)

    • Related Report
      2015 Research-status Report
  • [Journal Article] Structural basis for tumor necrosis factor blockade with the therapeutic antibody golimumab2018

    • Author(s)
      Ono Masatsugu、Horita Shoichiro、Sato Yumi、Nomura Yayoi、Iwata So、Nomura Norimichi
    • Journal Title

      Protein Science

      Volume: 印刷中 Issue: 6 Pages: 1038-1046

    • DOI

      10.1002/pro.3407

    • NAID

      120006471155

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The multidrug-resistance transporter MdfA from Escherichia coli: crystallization and X-ray diffraction analysis2017

    • Author(s)
      Nagarathinam Kumar、Jaenecke Frank、Nakada-Nakura Yoshiko、Hotta Yunhon、Liu Kehong、Iwata So、Stubbs Milton T.、Nomura Norimichi、Tanabe Mikio
    • Journal Title

      Acta Crystallographica Section F Structural Biology Communications

      Volume: 73 Issue: 7 Pages: 423-430

    • DOI

      10.1107/s2053230x17008500

    • NAID

      120006318883

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] High-resolution crystal structure of the therapeutic antibody pembrolizumab bound to the human PD-1.2016

    • Author(s)
      Horita S, Nomura Y, Sato Y, Shimamura T, Iwata S, Nomura N.
    • Journal Title

      Sci Rep.

      Volume: 6 Issue: 1 Pages: 35297-35297

    • DOI

      10.1038/srep35297

    • NAID

      120005850219

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The intervening removable affinity tag (iRAT) production system facilitates Fv antibody fragment-mediated crystallography.2016

    • Author(s)
      Nomura Y, Sato Y, Suno R, Horita S, Iwata S, Nomura N.
    • Journal Title

      Protein Sci.

      Volume: 25 Issue: 12 Pages: 2268-2276

    • DOI

      10.1002/pro.3035

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Structure and Molecular Mechanism of the Mammalian Fructose Transporter GLUT52016

    • Author(s)
      野村紀通,岩田想
    • Journal Title

      Nihon Kessho Gakkaishi

      Volume: 58 Issue: 3 Pages: 133-138

    • DOI

      10.5940/jcrsj.58.133

    • NAID

      130005159764

    • ISSN
      0369-4585, 1884-5576
    • Related Report
      2016 Research-status Report
    • Acknowledgement Compliant
  • [Journal Article] Structure and mechanism of the mammalian fructose transporter GLUT52015

    • Author(s)
      Nomura N, Verdon G, Kang HJ, Shimamura T, Nomura Y, Sonoda Y, Hussien SA, Qureshi AA, Coincon M, Sato Y, Abe H, Nakada-Nakura Y, Hino T, Arakawa T, Kusano-Arai O, Iwanari H, Murata T, Kobayashi T, Hamakubo T, Kasahara M, Iwata S, Drew D
    • Journal Title

      Nature

      Volume: 526 Issue: 7573 Pages: 397-401

    • DOI

      10.1038/nature14909

    • NAID

      120005657713

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Book] Bacterial Multidrug Exporters2017

    • Author(s)
      Jaenecke F., Nakada-Nakura, Y., Nagarathinam, K., Ogasawara, S., Liu, K., Hotta, Y., Iwata, S., Nomura, N., Tanabe, M
    • Total Pages
      355
    • Publisher
      Humana Press
    • ISBN
      9781493974528
    • Related Report
      2017 Annual Research Report
  • [Book] 糖尿病学2016(第4章「GLUT5の立体構造とフルクトース輸送機構」)2016

    • Author(s)
      野村紀通、岩田想
    • Total Pages
      161
    • Publisher
      診断と治療社
    • Related Report
      2016 Research-status Report
  • [Remarks] 京都大学大学院医学研究科分子細胞情報学分野

    • URL

      http://cell.mfour.med.kyoto-u.ac.jp/

    • Related Report
      2016 Research-status Report
  • [Remarks] 糖分を細胞内に輸送する膜たんぱく質の立体構造と動きを解明 -肥満やがんの抑制策に役立つ新たな知見-

    • URL

      http://www.kyoto-u.ac.jp/ja/research/research_results/2015/151001_1.html

    • Related Report
      2015 Research-status Report

URL: 

Published: 2015-04-16   Modified: 2019-03-29  

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