Updated on 2022/08/04

写真a

 
OSHIMA Atsunori
 
Organization
Cellular and Structural Physiology Institute Division Professor
Graduate School
Graduate School of Pharmaceutical Sciences
Title
Professor
Contact information
メールアドレス
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Degree 1

  1. 博士(理学) ( 2003.3   京都大学 ) 

 

Papers 31

  1. Structural insight into the activation mechanism of MrgD with heterotrimeric Gi-protein revealed by cryo-EM

    Suzuki Shota, Iida Momoko, Hiroaki Yoko, Tanaka Kotaro, Kawamoto Akihiro, Kato Takayuki, Oshima Atsunori

    COMMUNICATIONS BIOLOGY   Vol. 5 ( 1 ) page: 707   2022.7

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    Authorship:Last author, Corresponding author   Language:Japanese   Publisher:Communications Biology  

    MrgD, a member of the Mas-related G protein-coupled receptor (MRGPR) family, has high basal activity for Gi activation. It recognizes endogenous ligands, such as β-alanine, and is involved in pain and itch signaling. The lack of a high-resolution structure for MrgD hinders our understanding of whether its activation is ligand-dependent or constitutive. Here, we report two cryo-EM structures of the MrgD-Gi complex in the β-alanine-bound and apo states at 3.1 Å and 2.8 Å resolution, respectively. These structures show that β-alanine is bound to a shallow pocket at the extracellular domains. The extracellular half of the sixth transmembrane helix undergoes a significant movement and is tightly packed into the third transmembrane helix through hydrophobic residues, creating the active form. Our structures demonstrate a structural basis for the characteristic ligand recognition of MrgD. These findings provide a framework to guide drug designs targeting the MrgD receptor.

    DOI: 10.1038/s42003-022-03668-3

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  2. Structures of human pannexin-1 in nanodiscs reveal gating mediated by dynamic movement of the N terminus and phospholipids Reviewed International coauthorship

    Maki Kuzuya, Hidemi Hirano, Kenichi Hayashida, Masakatsu Watanabe, Kazumi Kobayashi, Tohru Terada, Md. Iqbal Mahmood, Florence Tama, Kazutoshi Tani, Yoshinori Fujiyoshi and Atsunori Oshima

    Science Signaling   Vol. 15 ( 720 ) page: eabg6941   2022.2

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    Authorship:Last author, Corresponding author   Language:Japanese   Publishing type:Research paper (scientific journal)  

    DOI: 10.1126/scisignal.abg6941

    Web of Science

  3. Cryo-EM structures of undocked innexin-6 hemichannels in phospholipids Reviewed

    Batuujin Burendei, Ruriko Shinozaki, Masakatsu Watanabe, Tohru Terada, Kazutoshi Tani, Yoshinori Fujiyoshi, and Atsunori Oshima

    Science Advances   Vol. 6 ( 7 ) page: eaax3157   2020.2

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1126/sciadv.aax3157

  4. Atomic structure of the innexin-6 gap junction channel determined by cryo-EM Reviewed

    Oshima, A., Tani, K. and Fujiyoshi, Y.

    Nature communications   Vol. 7   page: 13681   2016.12

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    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1038/ncomms13681

  5. Structural Basis for Binding of Potassium-Competitive Acid Blockers to the Gastric Proton Pump

    Tanaka Saki, Morita Mikio, Yamagishi Tatsuya, Madapally Hridya Valia, Hayashida Kenichi, Khandelia Himanshu, Gerle Christoph, Shigematsu Hideki, Oshima Atsunori, Abe Kazuhiro

    JOURNAL OF MEDICINAL CHEMISTRY   Vol. 65 ( 11 ) page: 7843 - 7853   2022.6

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    Language:Japanese   Publisher:Journal of medicinal chemistry  

    As specific inhibitors of the gastric proton pump, responsible for gastric acidification, K+-competitive acid blockers (P-CABs) have recently been utilized in the clinical treatment of gastric acid-related diseases in Asia. However, as these compounds have been developed based on phenotypic screening, their detailed binding poses are unknown. We show crystal and cryo-EM structures of the gastric proton pump in complex with four different P-CABs, tegoprazan, soraprazan, PF-03716556 and revaprazan, at resolutions reaching 2.8 Å. The structures describe molecular details of their interactions and are supported by functional analyses of mutations and molecular dynamics simulations. We reveal that revaprazan has a novel binding mode in which its tetrahydroisoquinoline moiety binds deep in the cation transport conduit. The mechanism of action of these P-CABs can now be evaluated at the molecular level, which will facilitate the rational development and improvement of currently available P-CABs to provide better treatment of acid-related gastrointestinal diseases.

    DOI: 10.1021/acs.jmedchem.2c00338

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  6. Structure and dynamics of Odinarchaeota tubulin and the implications for eukaryotic microtubule evolution Reviewed

    C. Akıl, S. Ali, L. T. Tran, J. Gaillard, W. Li, K. Hayashida, M. Hirose, T. Kato, A. Oshima, K. Fujishima, L. Blanchoin, A. Narita, R. C. Robinson

    Science Advances   Vol. 8 ( 12 ) page: eabm2225   2022.3

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1126/sciadv.abm2225

  7. Cryo-EM of the ATP11C flippase reconstituted in Nanodiscs shows a distended phospholipid bilayer inner membrane around transmembrane helix 2

    Nakanishi Hanayo, Hayashida Kenichi, Nishizawa Tomohiro, Oshima Atsunori, Abe Kazuhiro

    JOURNAL OF BIOLOGICAL CHEMISTRY   Vol. 298 ( 1 )   2022.1

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    Language:Japanese  

    DOI: 10.1016/j.jbc.2021.101498

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  8. A cryptic phosphate-binding pocket on the SPFH domain of human stomatin that regulates a novel fibril-like self-assembly

    Kataoka Koki, Suzuki Shota, Tenno Takeshi, Goda Natsuko, Hibino Emi, Oshima Atsunori, Hiroaki Hidekazu

    CURRENT RESEARCH IN STRUCTURAL BIOLOGY   Vol. 4   page: 158 - 166   2022

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    Language:Japanese   Publisher:Current Research in Structural Biology  

    Human stomatin (hSTOM) is a component of the membrane skeleton of erythrocytes that maintains the membrane's shape and stiffness through interconnecting spectrin and actin. hSTOM is a member of the protein family that possesses a single stomatin/prohibitin/flotillin/HflK (SPFH) domain at the center of the molecule. Although SPFH domain proteins are widely distributed from archaea to mammals, the detailed function of the domain remains unclear. In this study, we first determined the solution structure of the SPFH domain of hSTOM (hSTOM(SPFH)) via NMR. The solution structure of hSTOM(SPFH) is essentially identical to the already reported crystal structure of the STOM SPFH domain (mSTOM(SPFH)) of mice, except for the existence of a small hydrophilic pocket on the surface. We identified this pocket as a phosphate-binding site by comparing its NMR spectra with and without phosphate ions. Meanwhile, during the conventional process of protein NMR analysis, we eventually discovered that hSTOM(SPFH) formed a unique solid material after lyophilization. This lyophilized hSTOM(SPFH) sample was moderately slowly dissolved in a physiological buffer. Interestingly, it was resistant to dissolution against the phosphate buffer. We then found that the lyophilized hSTOM(SPFH) formed a fibril-like assembly under electron microscopy. Finally, we succeeded in reproducing this fibril-like assembly of hSTOM(SPFH) using a centrifugal ultrafiltration device, thus demonstrating that the increased protein concentration may promote self-assembly of hSTOM(SPFH) into fibril forms. Our observations may help understand the molecular function of the SPFH domain and its involvement in protein oligomerization as a component of the membrane skeleton. (245 words).

    DOI: 10.1016/j.crstbi.2022.05.002

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  9. Gastric proton pump with two occluded K+ engineered with sodium pump-mimetic mutations

    Abe Kazuhiro, Yamamoto Kenta, Irie Katsumasa, Nishizawa Tomohiro, Oshima Atsunori

    NATURE COMMUNICATIONS   Vol. 12 ( 1 )   2021.9

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  10. クライオ電子顕微鏡が加速するギャップ結合の構造研究 Invited

    大嶋篤典

    生体の科学   Vol. 71 ( 4 ) page: 315-320   2020.8

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    Authorship:Lead author   Language:Japanese  

  11. Presence of intrinsically disordered proteins can inhibit the nucleation phase of amyloid fibril formation of A beta(1-42) in amino acid sequence independent manner

    Ikeda Koki, Suzuki Shota, Shigemitsu Yoshiki, Tenno Takeshi, Goda Natsuko, Oshima Atsunori, Hiroaki Hidekazu

    SCIENTIFIC REPORTS   Vol. 10 ( 1 )   2020.7

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1038/s41598-020-69129-1

    Web of Science

  12. Structural insights into gap junction channels boosted by cryo-EM Invited Reviewed

    Atsunori Oshima

      Vol. 63   page: 42-48   2020.4

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    Authorship:Lead author   Language:English  

    DOI: 10.1016/j.sbi.2020.03.008

  13. Potential of cryo-EM for high-resolution structural analysis of gap junction channels Invited Reviewed

    Atsunori Oshima

    CURRENT OPINION IN STRUCTURAL BIOLOGY   Vol. 54   page: 78-85   2019.2

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1016/j.sbi.2019.01.005

    Web of Science

  14. イネキシンギャップ結合チャネルの原子分解能単粒子解析 Invited

    大嶋篤典

    顕微鏡   Vol. 52   page: 153-159   2017.12

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    Authorship:Lead author   Language:Japanese  

  15. Structure of an innexin gap junction channel and cryo-EM sample preparation Invited Reviewed

    Atsunori Oshima

    MICROSCOPY   Vol. 66 ( 6 ) page: 371-379   2017.12

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    Authorship:Lead author   Language:English  

    DOI: 10.1093/jmicro/dfx035

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  16. Hexadecameric structure of an invertebrate gap junction channel Reviewed

    Oshima, A., Matsuzawa, T., Murata, K., Tani, K. and Fujiyoshi, Y.

    J. Mol. Biol.   Vol. 428   page: 1227-1236   2016.3

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    DOI: 10.1016/j.jmb.2016.02.011.

  17. ギャップ結合チャネルの構造と多様性 Invited Reviewed

    大嶋篤典

    膜(MEMBRANE)   Vol. 41   page: 50-56   2016.3

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    Authorship:Lead author   Language:Japanese   Publishing type:Research paper (scientific journal)  

  18. GraDeR: membrane protein complex preparation for single particle cryo-EM. Reviewed

    Hauer, F., Gerle,C., Fischer, N., Oshima, A., Shinzawa-Itoh, K., Shimada, S., Yokoyama, K., Fujiyoshi, Y., Stark, H.

    Structure   Vol. 23   page: 1769-1775   2015.9

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  19. Structure and closure of connexin gap junction channels Invited Reviewed

    A. Oshima

    FEBS Letters   Vol. 588   page: 1230-1237   2014.2

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    Authorship:Lead author   Language:English  

  20. Oligomeric Structure and Functional Characterization of Caenorhabditis elegans Innexin-6 Gap Junction Protein Reviewed

    A. Oshima, T. Matsuzawa, K. Nishikawa, and Y. Fujiyoshi

    Journal of Biological Chemistry   Vol. 288   page: 10513-10521   2013.4

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  21. Asymmetric configurations and N-terminal rearrangements in connexin26 gap junction channels Reviewed

    A. Oshima, K. Tani, M. M. Toloue, Y. Hiroaki, A. Smock, S. Inukai, A. Cone, B. J. Nicholson ,G. E. Sosinsky, and Y. Fujiyoshi

    Journal of Molecular Biology     2011

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1016/j.jmb.2010.10.032

  22. Two-dimensional kinetics of inter-connexin interactions from single molecule force spectroscopy Reviewed

    F. Rico, A. Oshima, P. Hinterdorfer, Y. Fujiyoshi, and S. Scheuring

    Journal of Molecular Biology     2011

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1016/j.jmb.2011.07.013

  23. Analysis of four connexin26 mutant gap junctions and hemichannels reveals variations in hexamer stability Reviewed

    C. Ambrosi, D. Boassa, J. Pranskevich, A. Smock, A. Oshima, J. Xu, B. J. Nicholson ,G. E. Sosinsky

    Biophysical Journal     2010

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    DOI: 10.1016/j.bpj.2010.01.019

  24. 電子線結晶構造解析から導かれたギャップ結合チャネルのプラグゲーティング機構

    大嶋篤典

    顕微鏡   Vol. 44 ( 2 ) page: 87-92   2009

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

  25. The M34A mutant of Connexin26 reveals active conductance states in pore-suspending membranes Reviewed

    O. Gaßmann, M. Kreir, C. Ambrosi, J. Pranskevich, A. Oshima, C. Röling, G. Sosinsky, N. Fertig, and C. Steinem

    Journal of Structural Biology     2009

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1016/j.jsb.2009.02.004

  26. Structure of the connexin 26 gap junction channel at 3.5Å resolution Reviewed

    S. Maeda, S. Nakagawa, M. Suga, E. Yamashita, A. Oshima, Y. Fujiyoshi and T. Tsukihara

    Nature     2009

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1038/nature07869

  27. Projection structure of a N-terminal deletion mutant of connexin 26 channel with decreased central pore density Reviewed

    A. Oshima, K. Tani, Y. Hiroaki, Y. Fujiyoshi, and G. E. Sosinsky

    Cell Communication and Adhesion     2008

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1080/15419060802013588

  28. Three-dimensional structure of a human connexin26 gap junction channel reveals a plug in the vestibule Reviewed

    A. Oshima, K. Tani, Y. Hiroaki, Y. Fujiyoshi, and G. E. Sosinsky

    Proceedings of the National Academy of Sciences of the United States of America     2007

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    DOI: 10.1073/pnas.0703704104

  29. Mutation of a conserved threonine in the third transmembrane helix of and connexins creates a dominant-negative closed gap junction channel Reviewed

    D. Beahm, A. Oshima, G. M. Gaietta, G. M. Hand, A. E. Smock, S. N. Zucker, M. M. Toloue, A. Chandrasekhar, B. J. Nicholson, and G. E. Sosinsky

    Journal of Biological Chemistry     2006

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    DOI: 10.1074/jbc.M506533200

  30. Roles of Met-34, Cys-64, and Arg-75 in the assembly of human connexin 26. IMPLICATION FOR KEY AMINO ACID RESIDUES FOR CHANNEL FORMATION AND FUNCTION Reviewed

    A. Oshima, T. Doi, K. Mitsuoka, S. Maeda, and Y. Fujiyoshi

    Journal of Biological Chemistry     2003

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    DOI: 10.1074/jbc.M207713200

  31. The 11Å resolution projection map of Na+/K+-ATPase calculated by application of single particle analysis to two-dimensional crystal images Reviewed

    Y. Tahara, A. Oshima, T. Hirai, K. Mitsuoka, Y. Fujiyoshi, and Y. Hayashi

    Journal of Electron Microscopy   Vol. 49 ( 4 ) page: 583-587   2000

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MISC 1

  1. クライオ電子顕微鏡で見るギャップ結合チャネルの構造 Invited

    大嶋篤典

    細胞   Vol. 51   page: 8-11   2019

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    Authorship:Lead author   Language:Japanese  

Research Project for Joint Research, Competitive Funding, etc. 1

  1. クライオ電子顕微鏡のフィードバックに基づく膜タンパク質複合体の生産と技術支援

    2017.4 - 2022.3

    創薬等ライフサイエンス研究支援基盤事業 

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    Grant type:Competitive

KAKENHI (Grants-in-Aid for Scientific Research) 4

  1. 脂質二重膜中におけるlarge pore channelの新しい開閉モデルの探索

    Grant number:21K19215  2021.7 - 2023.3

    科学研究費助成事業  挑戦的研究(萌芽)

    大嶋 篤典

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    Authorship:Principal investigator 

    Grant amount:\6370000 ( Direct Cost: \4900000 、 Indirect Cost:\1470000 )

  2. 高等動物細胞間結合チャネルのクライオ電子顕微鏡構造研究

    Grant number:19H03165  2019.4 - 2022.3

    科学研究費助成事業  基盤研究(B)

    大嶋 篤典

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    Authorship:Principal investigator 

    Grant amount:\17290000 ( Direct Cost: \13300000 、 Indirect Cost:\3990000 )

    本研究はコネキシンギャップ結合チャネルの高分解能構造解析をクライオ電子顕微鏡単粒子解析法で行い、コネキシンチャネルの開閉機構と生理機能の解明に迫る。ヒトのコネキシン26とコネキシン32を対象とし、可溶化状態と脂質二重膜に再構成された状態のクライオ電子顕微鏡高分解能構造解析を行い、電気生理機能解析も併用する。また試料調製法の最適化による、膜タンパク質のクライオ電子顕微鏡高分解能構造解析を加速するための技術開発を目指す。
    多くの多細胞生物はギャップ結合チャネルと呼ばれる細胞間コミュニケーションを担う膜貫通構造を保持している。脊椎動物が保持するコネキシンギャップ結合チャネルの構造研究は結晶学的手法とクライオ電子顕微鏡法によって複数の報告がなされているが、その開閉機構についての構造基盤は明確には示されていない。
    本研究ではヒトが持つギャップ結合チャネルコネキシンの高分解能構造解析をクライオ電子顕微鏡単粒子解析で行い、コネキシンの開閉機構と生理機能の解明を目的としている。本年度はconnexin32(Cx32)の発現精製を行い、クライオ電子顕微鏡構造を得た。ナノディスクに再構成したCx32ギャップ結合チャネルとGraDeR法(Hauer et al. 2015)でフリーの界面活性剤ミセルを除去した可溶化状態のCx32ギャップ結合チャネルを調製し、単粒子解析法で、それぞれ3.9Å分解能、3.8Åで三次元再構成に成功した。可溶化状態のCx32は、そのN末端領域がチャネル通路に存在する可能性が高いが、マップの密度が乏しく、側鎖をアサインできるものではなかった。ナノディスクに再構成したCx32はN末端領域がチャネル通路の中で膜面に水平に存在しており、N末端領域の構造変化が示唆された。
    先の基盤研究Cから引き継いだナノディスクに再構成したINX-6ヘミチャネルのクライオ電子顕微鏡構造を論文にまとめ、発表した(Burendei et al. 2020, Sci. Adv. 6, eaax3157)。この論文では脂質がチャネル通路に入り込んで、開閉に寄与するモデルを提唱した。
    Cx32ギャップ結合チャネルの発現・精製は安定している。ナノディスク再構成とGraDeRの再現性も良く、クライオ電子顕微鏡用の試料は安定して供給できている。これまでデータ収集に用いたクライオ電子顕微鏡はマニュアル操作で大量データ収集が難しいが、試料の再現性が特に良いため、地道にデータを集めて分解能が4Åをようやく下回るところまで来ている。粒子の数が増えれば分解能の改善が期待される。
    本研究では、Cx32のN末端領域の密度が機能の議論に必須であるため、この部分のアミノ酸側鎖の分離が明確なマップにしたい。これまで粒子数が約14万粒子から計算して3.9Å分解能であるため、粒子数を増やして分解能を向上させる必要がある。自動データ収集機能を備えたクライオ電子顕微鏡を持つ研究機関と共同して100万粒子以上のデータセットから構造計算を行う予定である。また、Cx26も発現精製は確立しており、ナノディスク再構成とクライオ電子顕微鏡像の撮影を行う。

  3. High-resolution single particle analysis of intercellular channels

    Grant number:16K07266  2016.4 - 2019.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Oshima Atsunori

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    Authorship:Principal investigator 

    Grant amount:\4940000 ( Direct Cost: \3800000 、 Indirect Cost:\1140000 )

    We obtain the cryo-electron microscopy structures of Caenorhabditis elegans innexin-6 (INX-6) gap junction channels at atomic resolution. The INX-6 gap junction channel comprises hexadecameric subunits in an open state. The INX-6 structure is highly similar to the human connexin-26 structure, despite the lack of significant sequence similarity. We also have a hemichannel structures of INX-6 in a lipid nanodisc showing that flat double-layer densities obstruct the channel pore. Comparison of the hemichannel structures of a wild-type INX-6 in detergent and nanodisc-reconstituted N-terminal deletion mutant reveal that lipid-mediated N-terminal rearrangement and pore obstruction occur upon nanodisc reconstitution.Together with molecular dynamics simulations and electrophysiology functional assays, our results provide insight into how the large-size pore of gap junction hemichannels can be completely closed in a lipid bilayer.

  4. Studies in structural physiology of channels

    Grant number:15H05775  2015.5 - 2020.3

    FUJIYOSHI Yoshinori

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    Structural information of membrane proteins including channels is crucial toward gaining a better understanding of biologic functions. The information that can be gained from a protein structure strongly depends on its resolution - the higher the resolution, the more insight gained into the structure-function relationship of biologic macromolecules. We analyzed structures of proton pump, water channel AQP4, whose inhibitor could be a drug for brain edema, Na+ channel, gap junction channels and tight junction channels at high resolutions. While we could not get significant results of AChR, we analyzed structures of endothelin receptor and its complexes with the agonist and antagonists. In this project, we could get important knowledge in the research field named as structural physiology and partly elucidate how the channels work and regulate functions of the human body. We also contributed advancement of cryo-electron microscopy by developing cryo-electron microscopes.