Establishment of Theoretical Method of Predicting Thermostabilizing Mutations for Membrane Proteins
| Project/Area Number |
17H03663
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biophysics
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| Research Institution | Kyoto University |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2019: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2017: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
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| Keywords | 膜蛋白質 / G蛋白質共役型受容体 / ロドプシン / 耐熱化 / アミノ酸置換 / 統計熱力学 / 積分方程式論 / エントロピー / G蛋白質共役受容体 / 立体構造 |
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| Outline of Final Research Achievements |
For seven-transmembrane proteins, we developed a statistical-mechanical theory enabling us to evaluate the thermostability from the structures, microscopic geometric characteristics. An originality of the theory is the incorporation of effects of translational, configurational entropy of hydrocarbon groups within the lipid bilayer. We found that mutating the residue at a position of NBW=3.39 (NBW is the BW number) to Lys or Arg leads to substantially higher thermostability for significantly many GPCRs of Class A in the inactive state. The structures of some of them were newly determined. TR and XR or RxR and HsBR (rhodopsins) are quite different in the thermostability despite their high sequence similarity. These experimental facts could be elucidated by our theory.
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| Academic Significance and Societal Importance of the Research Achievements |
膜蛋白質は水環境中にある細胞外・細胞内領域と無極性環境中にある膜内領域から成り，水溶性蛋白質よりも複雑である。現在市販されている薬の60％以上が膜蛋白質を標的としているが，その安定性が低いため，立体構造決定や精製標品を用いた薬剤のスクリーニング系の開発が困難である。本研究によって，7回膜貫通ヘリックス構造を有する膜蛋白質の折り畳みの物理描像がほぼ完成され，かつ，アミノ酸置換による膜蛋白質の安定性向上を論理的に実現することが可能となった。各膜蛋白質に関連する生命機能や疾病原因の理解，様々な病気の治療薬の開発などに至る我が国のライフサイエンスの推進に大きく貢献できるものと考えられる。
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Report
(4 results)
Research Products
(62 results)
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[Journal Article] Structural Insights into the Subtype Selective Antagonist Binding to the M2 Muscarinic Receptor2018
Author(s)
R. Suno, S. Lee, S. Maeda, S. Yasuda, K. Yamashita, K. Hirata, S. Horita, M.S. Tawaramoto, H. Tsujimoto, T. Murata, M. Kinoshita, N. Vaidehi, M. Yamamoto, B. K. Kobilka, S. Iwata, T. Kobayashi
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Journal Title
Nature Chemical Biology
Volume: 14
Issue: 12
Pages: 1150-1158
DOI
NAID
Related Report
Peer Reviewed
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[Presentation] Theoretical prediction of thermostabilizing mutations for GPCR: Identification of hot-spot residues to be mutated common in Class A GPCRs2019
Author(s)
S. Yasuda, Y. Kajiwara, Y. Takamuku, N. Suzuki, Y. Toyoda, K. Morimoto, R. Suno, S. Iwata, T. Kobayashi, T. Murata, M. Kinoshita
Organizer
第57回日本生物物理学会年会
Related Report
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[Presentation] Structural insights into the subtype-selective antagonist binding to the M2 muscarinic receptor2019
Author(s)
R. Suno, S. Lee, S. Maeda, S. Yasuda, K. Yamashita, K. Hirata, T. Murata, M. Kinoshita, M. Yamamoto, B. Kobilka, N. Vaidehi, S. Iwata, T. Kobayashi
Organizer
第57回日本生物物理学会年会
Related Report
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[Presentation] Identification of thermostabilizing mutations for G-protein coupled receptors: Rapid method based on statistical thermodynamics2018
Author(s)
S. Yasuda, Y. Kajiwara, Y. Takamuku, N. Suzuki, Y. Toyoda, K. Morimoto, R. Suno, S. Iwata, T. Kobayashi, T. Murata, M. Kinoshita
Organizer
ImPACT野地プログラム国際シンポジウム“Artificial Cell Reactor Science and Technology”
Related Report
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