石田　英子 （イシダ　ハナコ）

Ishida, Hanako

写真a

所属（所属キャンパス）

薬学部 薬科学科 （芝共立）

職名

助教

HP
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経歴 【 表示 ／ 非表示 】

  • 2022年04月
    -
    継続中

    慶應義塾大学　薬学部, 助教

  • 2014年04月
    -
    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
    -
    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
    -
    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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学歴 【 表示 ／ 非表示 】

  • 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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  • KMN003 activates Nrf2 via disruption of the Keap1-Nrf2 interaction and p38-dependent transcriptional regulation

    Komeda K., Toyoshima K., Yasuda D., Ishida H., Kojima K., Osawa M., Hirano T., Ohe T., Tago K., Funakoshi-Tago M.

    Cellular Signalling 137 2026年01月

    ISSN  08986568

    　概要を見る

    Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that plays a crucial role in cellular defenses against oxidative stress and inflammation. Under normal conditions, Kelch-like ECH-associated protein 1 (Keap1), a ubiquitin ligase adaptor, binds to Nrf2, facilitating its ubiquitination and subsequent degradation via the proteasome. In this study, we investigated the properties of KMN003, a novel Nrf2 activator specifically designed to stabilize Nrf2 by disrupting its interaction with Keap1. X-ray crystallographic analysis revealed that KMN003 binds to the DGR-Cul3 (DC) domain of Keap1, occupying the Nrf2 interaction site. An AlphaScreen assay further showed that KMN003 effectively inhibits the binding between the Keap1 DC domain and the DLG motif of Nrf2 (IC₅₀ = 300 nM). We also investigated the mechanism of Nrf2 activation by KMN003 and its anti-inflammatory properties using murine macrophage-like RAW264.7 cells. KMN003 significantly reduced the lipopolysaccharide (LPS)-induced production of nitric oxide, CCL2, and tumor necrosis factor-alpha (TNFα) as well as the mRNA expression of inducible nitric oxide synthase, CCL2, and TNFα, which are essential inflammatory markers. KMN003 strongly inhibited nuclear translocation and transcriptional activation of nuclear factor-kappa B (NF-κB), a central regulator of inflammatory gene expression. KMN003 did not affect the LPS-induced phosphorylation of ERK or JNK, but strongly induced p38 phosphorylation in the absence of the LPS stimulation. The inhibition of p38 with SB203580 blocked KMN003-induced Nrf2 transcriptional activation despite promoting Nrf2 accumulation. These results highlight KMN003 as a promising anti-inflammatory drug that selectively stabilizes and activates Nrf2 via the p38 pathway.

  • Development of Keap1-Nrf2 Protein–Protein Interaction Inhibitor Activating Intracellular Nrf2 Based on the Naphthalene-2-acetamide Scaffold, and its Anti-Inflammatory Effects

    Yasuda D., Toyoshima K., Kojima K., Ishida H., Kaitoh K., Imamura R., Kanamitsu K., Kojima H., Funakoshi-Tago M., Osawa M., Ohe T., Hirano T.

    Chemmedchem 20 （ 21 ） e202500474 2025年11月

    ISSN  18607179

    　概要を見る

    Nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) axis is an attractive therapeutic target for various intractable diseases. Although protein–protein interaction inhibitors against Keap1-Nrf2 have been developed over the past decade, more structural expansion is needed to improve efficacy. In this article, several candidate compounds are designed and synthesized as novel Nrf2 activators and their intracellular Nrf2-activating effects are evaluated. Among the synthesized compounds, a novel naphthalene-1,4-(4-ethoxybenzensulfonamide) bearing a tertiary acetamide side chain at the 2-position strongly activated intracellular Nrf2. Particularly, the pyrrolidine-type acetamide compound showed the strongest intracellular Nrf2 activation. X-ray cocrystallography revealed that this compound can bind to the DC domain of Keap1. Additionally, the pyrrolidine-type acetamide compound induced the mRNA expression of the representative Nrf2 target genes heme oxygenase-1 and NAD(P)H:quinone oxidoreductase 1. Moreover, the compound exhibited anti-inflammatory effects in a lipopolysaccharide-stimulated macrophage cell line. Conclusively, these results suggest that the pyrrolidine-type naphthalene-2-acetamide is a promising compound for the development of Nrf2 activators that can be applied to treat inflammatory diseases.

  • Cryo-EM structures of the zinc transporters ZnT3 and ZnT4 provide insights into their transport mechanisms

    Ishida H, Yo R, Zhang Z, Shimizu T, Ohto U

    FEBS Letters 599 （ 1 ） 41 - 52 2024年10月

    研究論文（学術雑誌）, 筆頭著者, 査読有り,  ISSN  0014-5793

    　概要を見る

    Zinc transporters (ZnTs) act as H+/Zn2+ antiporters, crucial for zinc homeostasis. Brain-specific ZnT3 expressed in synaptic vesicles transports Zn2+ from the cytosol into vesicles and is essential for neurotransmission, with ZnT3 dysfunction associated with neurological disorders. Ubiquitously expressed ZnT4 localized to lysosomes facilitates the Zn2+ efflux from the cytosol to lysosomes, mitigating the cell injury risk. Despite their importance, the structures and Zn2+ transport mechanisms remain unclear. We characterized the three-dimensional structures of human ZnT3 (inward-facing) and ZnT4 (outward-facing) using cryo-electron microscopy. By combining these structures, we assessed the conformational changes that could occur within the transmembrane domain during Zn2+ transport. Our results provide a structural basis for a more comprehensive understanding of the H+/Zn2+ exchange mechanisms exhibited by ZnTs.

  • 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.

  • 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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  • 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

    [国内会議]  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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担当授業科目 【 表示 ／ 非表示 】

  • 課題研究（生命機能物理学）（春）

    2025年度

  • 課題研究（生命機能物理学）（秋）

    2025年度

  • 課題研究（生命機能物理学）

    2025年度

  • 演習（生命機能物理学）（春）

    2025年度

  • 演習（生命機能物理学）（秋）

    2025年度

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