慶應義塾研究者情報データベース

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• 2022年04月

  -

  継続中

  慶應義塾大学　薬学部, 助教

• 2014年04月

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  2022年03月

  東京大学大学院　薬学系研究科, 特任研究員

• 2011年10月

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  2014年03月

  大阪大学大学院　工学研究科, 技術補佐員

• 2009年02月

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  2011年09月

  株式会社カイオム・バイオサイエンス

• 2006年04月

  -

  2009年01月

  横浜市立大学大学院　国際総合科学科, 技術補佐員

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• 2004年04月

  -

  2006年03月

  鳥取大学, 農学部, 農学科

  大学院, 修了, 修士

• 2000年04月

  -

  2004年03月

  東京農業大学, 農学部, 農学科

  大学, 卒業

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• 博士（薬科学）, 東京大学, 論文, 2019年03月

  自然免疫受容体TLR9活性化機構の構造生物学的研究

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• Structure of the bile acid transporter and HBV receptor NTCP

  Asami J., Kimura K.T., Fujita-Fujiharu Y., Ishida H., Zhang Z., Nomura Y., Liu K., Uemura T., Sato Y., Ono M., Yamamoto M., Noda T., Shigematsu H., Drew D., Iwata S., Shimizu T., Nomura N., Ohto U.

  Nature （Nature)  606 （ 7916 ） 1021 - 1026 2022年06月

  研究論文（学術雑誌）, 査読有り,  ISSN  00280836

  　概要を見る

  Chronic infection with hepatitis B virus (HBV) affects more than 290 million people worldwide, is a major cause of cirrhosis and hepatocellular carcinoma, and results in an estimated 820,000 deaths annually1,2. For HBV infection to be established, a molecular interaction is required between the large glycoproteins of the virus envelope (known as LHBs) and the host entry receptor sodium taurocholate co-transporting polypeptide (NTCP), a sodium-dependent bile acid transporter from the blood to hepatocytes3. However, the molecular basis for the virus–transporter interaction is poorly understood. Here we report the cryo-electron microscopy structures of human, bovine and rat NTCPs in the apo state, which reveal the presence of a tunnel across the membrane and a possible transport route for the substrate. Moreover, the cryo-electron microscopy structure of human NTCP in the presence of the myristoylated preS1 domain of LHBs, together with mutation and transport assays, suggest a binding mode in which preS1 and the substrate compete for the extracellular opening of the tunnel in NTCP. Our preS1 domain interaction analysis enables a mechanistic interpretation of naturally occurring HBV-insusceptible mutations in human NTCP. Together, our findings provide a structural framework for HBV recognition and a mechanistic understanding of sodium-dependent bile acid translocation by mammalian NTCPs.

  • Access to Document (DOI)

• Structural basis for the oligomerization-mediated regulation of NLRP3 inflammasome activation

  Ohto U., Kamitsukasa Y., Ishida H., Zhangami K., Hirama C., Maekawa S., Shimizu T. Z., Murak

  Proceedings of the National Academy of Sciences of the United States of America （Proceedings of the National Academy of Sciences of the United States of America)  119 （ 11 ） e2121353119 2022年03月

  研究論文（学術雑誌）, 査読有り,  ISSN  00278424

  　概要を見る

  The nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) responds to a vast variety of stimuli, and activated NLRP3 forms an inflammasome, which in turn is associated with conditions such as atherosclerosis, Alzheimer's disease, and diabetes. A multilayered regulatory mechanism ensures proper NLRP3 inflammasome activation, although the structural basis for this process remains unclear. This study aimed to investigate the cryo-electron microscopy structure of the dodecameric form of full-length NLRP3 bound to the clinically relevant NLRP3-specific inhibitor MCC950. The inhibitor binds to the cavity distinct from the nucleotide binding site in the NACHT domain and stabilizes the closed conformation of NLRP3. The barrel-shaped dodecamer composed of the inactive form of NLRP3 is formed mainly through LRR-LRR interactions on the lateral side, and the highly positively charged top and bottom sides composed of NACHT domains provide a scaffold for membrane association. The cryo-electron microscopy structure suggests that oligomerization of NLRP3 is necessary for its membrane association; it is subsequently disrupted for activation, hence serving as a key player in controlling the spatiotemporal NLRP3 inflammasome activation. These findings are expected to contribute to the development of drugs targeting NLRP3 in future.

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• Cryo-EM structures of Toll-like receptors in complex with UNC93B1

  Ishida H., Asami J., Zhang Z., Nishizawa T., Shigematsu H., Ohto U., Shimizu T.

  Nature Structural and Molecular Biology （Nature Structural and Molecular Biology)  28 （ 2 ） 173 - 180 2021年02月

  研究論文（学術雑誌）, 査読有り,  ISSN  15459993

  　概要を見る

  Nucleic acid–sensing Toll-like receptors (TLRs) play a pivotal role in innate immunity by recognizing foreign DNA and RNA. Compartmentalization of these TLRs in the endosome limits their activation by self-derived nucleic acids and reduces the possibility of autoimmune reactions. Although chaperone Unc-93 homolog B1, TLR signaling regulator (UNC93B1) is indispensable for the trafficking of TLRs from the endoplasmic reticulum to the endosome, mechanisms of UNC93B1-mediated TLR regulation remain largely unknown. Here, we report two cryo-EM structures of human and mouse TLR3–UNC93B1 complexes and a human TLR7–UNC93B1 complex. UNC93B1 exhibits structural similarity to the major facilitator superfamily transporters. Both TLRs interact with the UNC93B1 amino-terminal six-helix bundle through their transmembrane and luminal juxtamembrane regions, but the complexes of TLR3 and TLR7 with UNC93B1 differ in their oligomerization state. The structural information provided here should aid in designing compounds to combat autoimmune diseases.

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• The effect of anesthetics on toll like receptor 9.

  Koutsogiannaki S, Bu W, Hou L, Shibamura-Fujiogi M, Ishida H, Ohto U, Eckenhoff RG, Yuki K

  FASEB journal : official publication of the Federation of American Societies for Experimental Biology 34 （ 11 ） 14645 - 14654 2020年11月

  研究論文（学術雑誌）, 査読有り,  ISSN  0892-6638

  • Access to Document (DOI)

• Homeostatic and pathogenic roles of GM3 ganglioside molecular species in TLR4 signaling in obesity.

  Kanoh H, Nitta T, Go S, Inamori KI, Veillon L, Nihei W, Fujii M, Kabayama K, Shimoyama A, Fukase K, Ohto U, Shimizu T, Watanabe T, Shindo H, Aoki S, Sato K, Nagasaki M, Yatomi Y, Komura N, Ando H, Ishida H, Kiso M, Natori Y, Yoshimura Y, Zonca A, Cattaneo A, Letizia M, Ciampa M, Mauri L, Prinetti A, Sonnino S, Suzuki A, Inokuchi JI

  The EMBO journal 39 （ 12 ） e101732 2020年06月

  研究論文（学術雑誌）, 査読有り,  ISSN  0261-4189

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• Erratum: Structural basis for the oligomerization-mediated regulation of NLRP3 inflammasome activation (Proceedings of the National Academy of Sciences of the United States of America 119 (e2121353119) DOI: 10.1073/pnas.2121353119)

  Ohto U., Kamitsukasa Y., Ishida H., Zhang Z., Murakami K., Hirama C., Maekawa S., Shimizu T.

  Proceedings of the National Academy of Sciences of the United States of America (Proceedings of the National Academy of Sciences of the United States of America)  119 ( 18 )  2022年05月

  ISSN  00278424

  　概要を見る

  The authors note that Figs. S4 and S6 in the SI Appendix appeared incorrectly. A figure section from Fig. S4 and some labels from Fig. S6 were removed during conversion from Word to PDF. The SI Appendix has been corrected online.

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• 核酸認識TLRの活性化および輸送機構の構造基盤

  石田英子

  日本分子生物学会年会 (神戸ポートアイランド) , 

  2023年12月

  , 

  口頭発表（招待・特別）, 日本分子生物学会年会事務局

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• 課題研究（生命機能物理学）

  2024年度

• 演習（生命機能物理学）

  2024年度

• 卒業研究１（薬学科）

  2024年度

• 物理化学３

  2024年度

• 英語演習（薬学科）

  2024年度

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