横川　真梨子 （ヨコガワ　マリコ）

YOKOGAWA Mariko

写真a

所属（所属キャンパス）

薬学部 薬科学科 生命機能物理学講座 （芝共立）

職名

専任講師

外部リンク
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学位 【 表示 ／ 非表示 】

  • 博士（薬学）, 東京大学, 課程

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免許・資格 【 表示 ／ 非表示 】

  • 薬剤師免許

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研究分野 【 表示 ／ 非表示 】

  • ライフサイエンス / 薬系分析、物理化学

  • ライフサイエンス / 構造生物化学

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研究キーワード 【 表示 ／ 非表示 】

  • NMR

  • イオンチャネル

  • ウイルス感染症

  • 構造生物学

  • 翻訳因子

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著書 【 表示 ／ 非表示 】

  • Peptide Toxins Targeting KV Channels

    Matsumura K., Yokogawa M., Osawa M., Handbook of Experimental Pharmacology, 2021年

    　概要を見る

    A number of peptide toxins isolated from animals target potassium ion (K+) channels. Many of them are particularly known to inhibit voltage-gated K+ (KV) channels and are mainly classified into pore-blocking toxins or gating-modifier toxins. Pore-blocking toxins directly bind to the ion permeation pores of KV channels, thereby physically occluding them. In contrast, gating-modifier toxins bind to the voltage-sensor domains of KV channels, modulating their voltage-dependent conformational changes. These peptide toxins are useful molecular tools in revealing the structure-function relationship of KV channels and have potential for novel treatments for diseases related to KV channels. This review focuses on the inhibition mechanism of pore-blocking and gating-modifier toxins that target KV channels.

  • Nuclear magnetic resonance approaches for characterizing protein-protein interactions

    Toyama Y., Mase Y., Kano H., Yokogawa M., Osawa M., Shimada I., Methods in Molecular Biology, 2018年

    　概要を見る

    The gating of potassium ion (K+) channels is regulated by various kinds of protein-protein interactions (PPIs). Structural investigations of these PPIs provide useful information not only for understanding the gating mechanisms of K+ channels, but also for developing the pharmaceutical compounds targeting K+ channels. Here, we describe a nuclear magnetic resonance spectroscopic method, termed the cross saturation (CS) method, to accurately determine the binding surfaces of protein complexes, and its application to the investigation of the interaction between a G protein-coupled inwardly rectifying K+ channel and a G protein α subunit.

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論文 【 表示 ／ 非表示 】

  • Ribonuclease inhibitor and angiogenin system regulates cell type–specific global translation

    Stillinovic M., Sarangdhar M.A., Andina N., Tardivel A., Greub F., Bombaci G., Ansermet C., Zatti M., Saha D., Xiong J., Sagae T., Yokogawa M., Osawa M., Heller M., Keogh A., Keller I., Angelillo-Scherrer A., Allam R.

    Science Advances （Science Advances）  10 （ 22 ） eadl0320 2024年05月

    　概要を見る

    Translation of mRNAs is a fundamental process that occurs in all cell types of multicellular organisms. Conventionally, it has been considered a default step in gene expression, lacking specific regulation. However, recent studies have documented that certain mRNAs exhibit cell type–specific translation. Despite this, it remains unclear whether global translation is controlled in a cell type–specific manner. By using human cell lines and mouse models, we found that deletion of the ribosome-associated protein ribonuclease inhibitor 1 (RNH1) decreases global translation selectively in hematopoietic-origin cells but not in the non–hematopoietic-origin cells. RNH1-mediated cell type–specific translation is mechanistically linked to angiogenin-induced ribosomal biogenesis. Collectively, this study unravels the existence of cell type–specific global translation regulators and highlights the complex translation regulation in vertebrates.

  • Applying deep learning to iterative screening of medium-sized molecules for protein-protein interaction-targeted drug discovery

    Shimizu Y., Yonezawa T., Bao Y., Sakamoto J., Yokogawa M., Furuya T., Osawa M., Ikeda K.

    Chemical Communications （Chemical Communications）  59 （ 44 ） 6722 - 6725 2023年05月

    ISSN  13597345

    　概要を見る

    We combined a library of medium-sized molecules with iterative screening using multiple machine learning algorithms that were ligand-based, which resulted in a large increase of the hit rate against a protein-protein interaction target. This was demonstrated by inhibition assays using a PPI target, Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 (Keap1/Nrf2), and a deep neural network model based on the first-round assay data showed a highest hit rate of 27.3%. Using the models, we identified novel active and non-flat compounds far from public datasets, expanding the chemical space.

  • TDP-43 N-terminal domain dimerisation or spatial separation by RNA binding decreases its propensity to aggregate

    Miura M., Sakaue F., Matsuno H., Morita K., Yoshida A., Hara R.I., Nishimura R., Nishida Y., Yokogawa M., Osawa M., Yokota T.

    FEBS Letters （FEBS Letters）  597 （ 12 ） 1667 - 1676 2023年

    ISSN  00145793

    　概要を見る

    Aggregation of the 43 kDa TAR DNA-binding protein (TDP-43) is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). RNA binding and TDP-43 N-terminal domain dimerisation has been suggested to ameliorate TDP-43 aggregation. However, the relationship between these factors and the solubility of TDP-43 is largely unknown. Therefore, we developed new oligonucleotides that can recruit two TDP-43 molecules and interfere with their intermolecular interactions via spatial separation. Using these oligonucleotides and TDP-43-preferable UG-repeats, we uncovered two distinct mechanisms for modulating TDP-43 solubility by RNA binding: One is N-terminal domain dimerisation, and the other is the spatial separation of two TDP-43 molecules. This study provides new molecular insights into the regulation of TDP-43 solubility.

  • Paip2A inhibits translation by competitively binding to the RNA recognition motifs of PABPC1 and promoting its dissociation from the poly(A) tail.

    Sagae T, Yokogawa M, Sawazaki R, Ishii Y, Hosoda N, Hoshino SI, Imai S, Shimada I, Osawa M

    The Journal of biological chemistry （Journal of Biological Chemistry）  298 （ 5 ） 101844 2022年03月

    ISSN  0021-9258

    　概要を見る

    Eukaryotic mRNAs possess a poly(A) tail at their 30-end, to which poly(A)-binding protein C1 (PABPC1) binds and recruits other proteins that regulate translation. Enhanced poly(A)dependent translation, which is also PABPC1 dependent, promotes cellular and viral proliferation. PABP-interacting protein 2A (Paip2A) effectively represses poly(A)-dependent translation by causing the dissociation of PABPC1 from the poly(A) tail; however, the underlying mechanism remains unknown. This study was conducted to investigate the functional mechanisms of Paip2A action by characterizing the PABPC1–poly(A) and PABPC1–Paip2A interactions. Isothermal titration calorimetry and NMR analyses indicated that both interactions predominantly occurred at the RNA recognition motif (RRM) 2–RRM3 regions of PABPC1, which have comparable affinities for poly(A) and Paip2A (dissociation constant, Kd = 1 nM). However, the Kd values of isolated RRM2 were 200 and 4 μM in their interactions with poly(A) and Paip2A, respectively; Kd values of 5 and 1 μM were observed for the interactions of isolated RRM3 with poly(A) and Paip2A, respectively. NMR analyses also revealed that Paip2A can bind to the poly(A)binding interfaces of the RRM2 and RRM3 regions of PABPC1. Based on these results, we propose the following functional mechanism for Paip2A: Paip2A initially binds to the RRM2 region of poly(A)-bound PABPC1, and RRM2-anchored Paip2A effectively displaces the RRM3 region from poly(A), resulting in dissociation of the whole PABPC1 molecule. Together, our findings provide insight into the translation repression effect of Paip2A and may aid in the development of novel anticancer and/or antiviral drugs.

  • Mechanism of hERG inhibition by gating-modifier toxin, APETx1, deduced by functional characterization

    Matsumura K., Shimomura T., Kubo Y., Oka T., Kobayashi N., Imai S., Yanase N., Akimoto M., Fukuda M., Yokogawa M., Ikeda K., Kurita J.i., Nishimura Y., Shimada I., Osawa M.

    BMC Molecular and Cell Biology （BMC Molecular and Cell Biology）  22 （ 3 ） 3 2021年01月

    研究論文（学術雑誌）, 共著, 査読有り

    　概要を見る

    Background: Human ether-à-go-go-related gene potassium channel 1 (hERG) is a voltage-gated potassium channel, the voltage-sensing domain (VSD) of which is targeted by a gating-modifier toxin, APETx1. APETx1 is a 42-residue peptide toxin of sea anemone Anthopleura elegantissima and inhibits hERG by stabilizing the resting state. A previous study that conducted cysteine-scanning analysis of hERG identified two residues in the S3-S4 region of the VSD that play important roles in hERG inhibition by APETx1. However, mutational analysis of APETx1 could not be conducted as only natural resources have been available until now. Therefore, it remains unclear where and how APETx1 interacts with the VSD in the resting state. Results: We established a method for preparing recombinant APETx1 and determined the NMR structure of the recombinant APETx1, which is structurally equivalent to the natural product. Electrophysiological analyses using wild type and mutants of APETx1 and hERG revealed that their hydrophobic residues, F15, Y32, F33, and L34, in APETx1, and F508 and I521 in hERG, in addition to a previously reported acidic hERG residue, E518, play key roles in the inhibition of hERG by APETx1. Our hypothetical docking models of the APETx1-VSD complex satisfied the results of mutational analysis. Conclusions: The present study identified the key residues of APETx1 and hERG that are involved in hERG inhibition by APETx1. These results would help advance understanding of the inhibitory mechanism of APETx1, which could provide a structural basis for designing novel ligands targeting the VSDs of KV channels.

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総説・解説等 【 表示 ／ 非表示 】

  • Nuclear Magnetic Resonance Approaches for Characterizing Protein-Protein Interactions.

    Toyama Y, Mase Y, Kano H, Yokogawa Mariko, Osawa M, Shimada I

    Methods Mol Biol. 1684   115 - 128 2018年10月

    記事・総説・解説・論説等（学術雑誌）, 共著

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研究発表 【 表示 ／ 非表示 】

  • Structural insights into the inhibitory mechanism of transcription factor FOXO3a by phosphorylation and 14-3-3ζ

    榎本翔太，桑山知也，中塚将一，横川真梨子，河津光作，中村吏佐，木村友美，田辺幹雄，千田俊哉，齋藤潤，佐谷秀行，大澤匡範

    第46回日本分子生物学会年会 （神戸ポートアイランド） , 

    2023年12月
    , 

    ポスター発表

  • Structural mechanism for the acceleration of the Caf1-dependent deadenylation of mRNA by BTG2

    片岡奈緒，横川真梨子，石井裕一郎，城えりか，高嶋大翔，沢崎綾一，寒河江彪流，尾上耕一，星野真一，大澤匡範

    第46回日本分子生物学会年会 （神戸ポートアイランド） , 

    2023年12月
    , 

    ポスター発表

  • タンパク質-タンパク質相互作用をターゲットとした感染阻害大環状物質の探索と構造活性相関解析

    米澤朋起，清水祐吾，池田和由，山本雄一朗，野口耕司，酒井祥太，深澤征義，横川真梨子，大澤匡範

    第51回構造活性相関シンポジウム （日本薬学会長井記念ホール） , 

    2023年11月
    , 

    口頭発表（一般）, 日本薬学会構造活性相関部会

  • NMR解析により得られたKeap1-Nrf2のPPI阻害化合物のKeap1結合の構造基盤

    小島行人，石田英子，原田彩佳，米澤朋起，清水祐吾，池田和由，横川真梨子，大澤匡範

    第62回NMR討論会 （横須賀芸術劇場） , 

    2023年11月
    , 

    ポスター発表

  • hACE2に結合してSARS-CoV-2の侵入を阻害する化合物の創製

    横川 真梨子, 堀内 まほろ, 金一 駿希, 大竹 帝河, 米澤 朋起, 清水 祐吾, 池田 和由, 山 本 雄一朗, 酒井 祥太, 野口 耕司, 深澤 征義, 大澤 匡範

    第62回NMR討論会 （横須賀芸術劇場） , 

    2023年11月
    , 

    ポスター発表

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競争的研究費の研究課題 【 表示 ／ 非表示 】

  • B型肝炎ウイルスの肝細胞侵入・増殖機構の構造基盤と立体構造に基づく創薬

    2021年04月
    -
    2024年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 横川 真梨子, 基盤研究(C), 補助金,  研究代表者

  • B型肝炎ウイルスの肝細胞侵入および増殖機構の構造生物学的解析

    2018年04月
    -
    2021年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 横川　真梨子, 基盤研究(C), 補助金,  研究代表者

  • B型肝炎ウイルスの感染機構の構造基盤

    2016年04月
    -
    2018年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 横川　真梨子, 若手研究(B), 補助金,  研究代表者

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担当授業科目 【 表示 ／ 非表示 】

  • 物理化学３

    2024年度

  • 物理分析学

    2024年度

  • 英語演習（薬学科）

    2024年度

  • 英語演習（薬科学科）

    2024年度

  • 早期体験学習（薬科学科）

    2024年度

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担当経験のある授業科目 【 表示 ／ 非表示 】

  • 薬学基礎実習

    慶應義塾

    2015年04月
    -
    2016年03月
    , 

    秋学期, 実習・実験

  • C1(4)物質の変化

    慶應義塾

    2015年04月
    -
    2016年03月
    , 

    秋学期, 講義

    反応速度

  • 薬学実習IIA（化学、物理）

    慶應義塾

    2015年04月
    -
    2016年03月
    , 

    春学期, 実習・実験

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