2021 Fiscal Year Final Research Report
Elucidation of the mechanisms of action of the anti-rheumatic drug MTX in the inflammatory signaling pathway based on its target protein structure information
| Project/Area Number |
19K07011
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 47020:Pharmaceutical analytical chemistry and physicochemistry-related
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| Research Institution | Akita University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
面川 歩 秋田大学, 医学部附属病院, 助教 (80722066)
刈屋 佑美 秋田大学, 産学連携推進機構, 講師 (10779002)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | メトトレキサート / 抗リウマチ薬 / 炎症性疾患 / マクロファージ遊走阻止因子 / 中性子結晶構造解析 / X線結晶構造解析 / 分子動力学シミュレーション |
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| Outline of Final Research Achievements |
Methotrexate (MTX) is currently used as the anchor drug in the treatment of rheumatoid arthritis (RA). However, the mechanisms of action of MTX in the RA therapy are not fully understood. We have previously identified macrophage migration inhibitory factor (MIF) as a novel MTX-binding protein. MIF is a widely expressed pro-inflammatory cytokine that plays crucial roles in the regulation of inflammation. MIF signal transduction is initiated by binding to CD74 and stimulates ERK1/2 MAPK cascade, resulting in the production of various inflammatory cytokines such as TNF-a. In this study, we report effects of MTX on the formation of MIF-CD74 complex. MD simulations and MM-GBSA calculations with the MTX-MIF complex and the extracellular domain of CD74 structures showed the MTX binding decreased the stability of the MIF-CD74 complex. Neutron structure of MIF reveals two hydrogen bonding networks for the MTX binding in the MIF structure.
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| Free Research Field |
構造生物学
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| Academic Significance and Societal Importance of the Research Achievements |
関節リウマチ治療におけるMTXの作用機序の一つとして、MTXがMIF-CD74複合体の形成を阻害し、その結果、抗炎症作用を発揮する可能性を示すことができた。今後更に研究を発展させ、MTXの作用機序の理解が進めば、MTXの改良と治療効果の早期評価系の確立に貢献できると考えられる。また、中性子結晶構造解析により、水素原子を含む原子レベルでMIFの立体構造を明らかにすることができた。MIFは多くの炎症性疾患に関与することから、潜在的な治療標的となっている。本研究で得られたMIFの精微な構造情報に基づき、MIFを標的とする新規薬剤開発が可能となることから、国民の健康維持への貢献が期待できる。
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