Yokogawa, Mariko

写真a

Affiliation

Faculty of Pharmacy, Department of Pharmaceutical Sciences 生命機能物理学講座 （Shiba-Kyoritsu）

Position

Assistant Professor/Senior Assistant Professor

External Links
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Academic Degrees 【 Display / hide 】

  • 博士（薬学）, The University of Tokyo, Coursework

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Licenses and Qualifications 【 Display / hide 】

  • 薬剤師免許

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Research Areas 【 Display / hide 】

  • Life Science / Pharmaceutical analytical chemistry and physicochemistry

  • Life Science / Structural biochemistry

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Research Keywords 【 Display / hide 】

  • NMR

  • イオンチャネル

  • 構造生物学

  • 膜タンパク質

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Books 【 Display / hide 】

  • Peptide Toxins Targeting KV Channels

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

    　View Summary

    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

    　View Summary

    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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Papers 【 Display / hide 】

  • 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 2023.05

    ISSN  13597345

    　View Summary

    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

    ISSN  00145793

    　View Summary

    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 2022.03

    ISSN  0021-9258

    　View Summary

    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 2021.01

    Research paper (scientific journal), Joint Work, Accepted

    　View Summary

    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.

  • Structural mechanism underlying G protein family-specific regulation of G protein-gated inwardly rectifying potassium channel

    Kano H., Toyama Y., Imai S., Iwahashi Y., Mase Y., Yokogawa M., Osawa M., Shimada I.

    Nature Communications 10 （ 1 ）  2019.12

    Research paper (scientific journal), Joint Work, Accepted

    　View Summary

    G protein-gated inwardly rectifying potassium channel (GIRK) plays a key role in regulating neurotransmission. GIRK is opened by the direct binding of the G protein βγ subunit (Gβγ), which is released from the heterotrimeric G protein (Gαβγ) upon the activation of G protein-coupled receptors (GPCRs). GIRK contributes to precise cellular responses by specifically and efficiently responding to the Gi/o-coupled GPCRs. However, the detailed mechanisms underlying this family-specific and efficient activation are largely unknown. Here, we investigate the structural mechanism underlying the Gi/o family-specific activation of GIRK, by combining cell-based BRET experiments and NMR analyses in a reconstituted membrane environment. We show that the interaction formed by the αA helix of Gαi/o mediates the formation of the Gαi/oβγ-GIRK complex, which is responsible for the family-specific activation of GIRK. We also present a model structure of the Gαi/oβγ-GIRK complex, which provides the molecular basis underlying the specific and efficient regulation of GIRK.

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Papers, etc., Registered in KOARA 【 Display / hide 】

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Reviews, Commentaries, etc. 【 Display / hide 】

  • 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 2018.10

    Article, review, commentary, editorial, etc. (scientific journal), Joint Work

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Presentations 【 Display / hide 】

  • NMR-based drug design of the entry inhibitor of SARS-CoV-2 targeting the interaction between SARS-CoV-2 spike protein and hACE2

    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23回日本蛋白質科学会年会 (名古屋国際会議場) , 

    2023.07
    , 

    Poster presentation

  • NMR-based drug design of the entry inhibitor of SARS-CoV-2 targeting the interaction between SARS-CoV-2 spike protein and hACE2

    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

    日本薬学会第143年会 (北海道大学) , 

    2023.03
    , 

    Poster presentation

  • Structural basis for the inhibition mechanism of hepatitis B virus infection by oolonghomobisflavan C

    石場 智彬, 横川 真梨子, 横田 旭美, 大澤 匡範

    日本薬学会第143回年会 (北海道大学) , 

    2023.03
    , 

    Poster presentation

  • COVID-19の原因となるタンパク質-タンパク質相互作用を標的とする合成中分子阻害剤のインシリコスクリーニング

    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

    日本薬学会第143年会 (札幌) , 

    2023.03
    , 

    Poster presentation

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

    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61回NMR討論会 (高知県立県民文化ホール（高知県高知市）) , 

    2022.11
    , 

    Poster presentation

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Research Projects of Competitive Funds, etc. 【 Display / hide 】

  • 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

    2021.04
    -
    2024.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

  • 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

    2018.04
    -
    2021.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

  • Structural basis for hepatitis B virus infection

    2016.04
    -
    2018.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Young Scientists (B), Principal investigator

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Courses Taught 【 Display / hide 】

  • STUDY OF MAJOR FIELD:(PHYSICS FOR LIFE FUNCTIONS)

    2023

  • SEMINAR:(PHYSICS FOR LIFE FUNCTIONS)

    2023

  • RESEARCH FOR BACHELOR'S THESIS 1

    2023

  • RESEARCH APPARATUS LABORATORY COURSE

    2023

  • PHYSICAL CHEMISTRY 3

    2023

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Courses Previously Taught 【 Display / hide 】

  • 薬学基礎実習

    Keio University

    2015.04
    -
    2016.03
    , 

    Autumn Semester, Laboratory work/practical work/exercise

  • C1(4)物質の変化

    Keio University

    2015.04
    -
    2016.03
    , 

    Autumn Semester, Lecture

    反応速度

  • 薬学実習IIA（化学、物理）

    Keio University

    2015.04
    -
    2016.03
    , 

    Spring Semester, Laboratory work/practical work/exercise

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