Structural basis of signal transduction mediated by various GPCRs
Project/Area Number |
17H04999
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Research Category |
Grant-in-Aid for Young Scientists (A)
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Allocation Type | Single-year Grants |
Research Field |
Structural biochemistry
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Research Institution | The University of Tokyo |
Principal Investigator |
Kofuku Yutaka 東京大学, 大学院薬学系研究科(薬学部), 助教 (80737940)
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Project Period (FY) |
2017-04-01 – 2021-03-31
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Project Status |
Completed (Fiscal Year 2020)
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Budget Amount *help |
¥26,130,000 (Direct Cost: ¥20,100,000、Indirect Cost: ¥6,030,000)
Fiscal Year 2020: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2019: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2018: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2017: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
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Keywords | 核磁気共鳴法 / シグナル伝達 / 膜タンパク質 / Gタンパク質共役型受容体 / 脂質二重膜 / 薬学 / 生物物理 / 蛋白質 / 免疫学 / 構造生物学 |
Outline of Final Research Achievements |
G-protein-coupled receptors (GPCRs) are seven-transmembrane proteins mediating cellular signals in response to extracellular stimuli. Although three-dimensional structures showcase snapshots that can be sampled in the process, the mechanism by which agonist-activated GPCRs interact with various effectors remains elusive. Here, we used nuclear magnetic resonance to visualize the structures of beta2-adrenergic receptor and adenosine A2A receptor. Analyses of efficacy-dependent chemical shifts of beta2-adrenergic receptor identified an equilibrium among three conformations, including one responsible for the varied signal level in each ligand-bound state. The docosahexanoic acid chains in lipid membranes redistribute the multiple conformations of adenosine A2A receptor toward those preferable for G protein binding. These results provide a structural basis for the dynamic activation of GPCRs and shed light on GPCR-mediated signal transduction.
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Academic Significance and Societal Importance of the Research Achievements |
医薬品の30%以上は、G蛋白質共役型受容体(GPCR)に作用して、シグナル伝達活性を変化させることで、治療効果を発揮する。本研究で得られたGPCRの構造を参考にして、下流のシグナルを伝達する分子との相互作用に、選択的に作用する化合物を作ることができれば、副作用を抑制する薬剤を、合理的に設計できる可能性が示された。また、脂質の作用を模倣することで、生体内に存在する化合物や他の薬剤がすでに結合したGPCRに対しても作用する薬剤設計の道が開け、新たな作用点および薬理作用を持つ医薬品の開発が加速することが期待される。
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Report
(5 results)
Research Products
(19 results)
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[Journal Article] Deuteration and Selective Labeling of Alanine Methyl Groups of β 2-Adrenergic Receptor Expressed in a Baculovirus-Insect Cell Expression System2018
Author(s)
Yutaka Kofuku, Tomoki Yokomizo, Shunsuke Imai, Yutaro Shiraishi, Mei Natsume, Hiroaki Itoh, Masayuki Inoue, Kunio Nakata, Shunsuke Igarashi, Hideyuki Yamaguchi, Toshimi Mizukoshi, Ei-Ichiro Suzuki, Takumi Ueda, Ichio Shimada
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Journal Title
Journal of Biomolecular NMR
Volume: 印刷中
Issue: 3
Pages: 185-192
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] Dynamics of G protein-coupled receptor related to various signaling revealed by NMR2019
Author(s)
Kofuku Y, Shiraishi Y, Natsume M, Okude J, Sato M, Imai S, Kondo K, Mizumura T, Maeda M, Tsujishita H, Kuranaga T, Inoue M, Nakata K, Mizukoshi T, Ueda T, Iwai H, Shimada I
Organizer
第57回日本生物物理学会年会
Related Report
Invited
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[Presentation] Deuteration and selective labeling of alanine methyl groups of β2-adrenergic receptor expressed in a baculovirus-insect cell expression system2018
Author(s)
Yutaka Kofuku, Tomoki Yokomizo, Shunsuke Imai, Yutaro Shiraishi, Mei Natsume, Hiroaki Itoh, Masayuki Inoue, Kunio Nakata, Shunsuke Igarashi, Hideyuki Yamaguchi, Toshimi Mizukoshi, Ei-Ichiro Suzuki, Takumi Ueda and Ichio Shimada
Organizer
XXVIII International Conference on Magnetic Resonance in Biological Systems
Related Report
Int'l Joint Research
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