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  Real-time tracking of drug binding to influenza A M2 reveals a high energy barrier

Tekwani Movellan, K., Wegstroth, M., Overkamp, K., Leonov, A., Becker, S., & Andreas, L. B. (2023). Real-time tracking of drug binding to influenza A M2 reveals a high energy barrier. Journal of Structural Biology: X, 8:. doi:10.1016/j.yjsbx.2023.100090.

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アイテムのパーマリンク: https://hdl.handle.net/21.11116/0000-000D-B901-1 版のパーマリンク: https://hdl.handle.net/21.11116/0000-000D-B902-0
資料種別: 学術論文

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1-s2.0-S2590152423000065-main.pdf (出版社版), 4MB
ファイルのパーマリンク:
https://hdl.handle.net/21.11116/0000-000D-B903-F
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1-s2.0-S2590152423000065-main.pdf
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Version of Record 15 June 2023
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Gold
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公開
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application/pdf / [MD5]
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 作成者:
Tekwani Movellan, Kumar1, 著者           
Wegstroth, Melanie1, 著者           
Overkamp, Kerstin1, 著者           
Leonov, A.1, 著者           
Becker, Stefan1, 著者           
Andreas, Loren B.1, 著者           
所属:
1Department of NMR Based Structural Biology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society, ou_3350124              

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 要旨: The drug Rimantadine binds to two different sites in the M2 protein from influenza A, a peripheral site and a pore site that is the primary site of efficacy. It remained enigmatic that pore binding did not occur in certain detergent micelles, and in particular incomplete binding was observed in a mixture of lipids selected to match the viral membrane. Here we show that two effects are responsible, namely changes in the protein upon pore binding that prevented detergent solubilization, and slow binding kinetics in the lipid samples. Using 55–100 kHz magic-angle spinning NMR, we characterize kinetics of drug binding in three different lipid environments: DPhPC, DPhPC with cholesterol and viral mimetic membrane lipid bilayers. Slow pharmacological binding kinetics allowed the characterization of spectral changes associated with non-specific binding to the protein periphery in the kinetically trapped pore-apo state. Resonance assignments were determined from a set of proton-detected 3D spectra. Chemical shift changes associated with functional binding in the pore of M2 were tracked in real time in order to estimate the activation energy. The binding kinetics are affected by pH and the lipid environment and in particular cholesterol. We found that the imidazole-imidazole hydrogen bond at residue histidine 37 is a stable feature of the protein across several lipid compositions. Pore binding breaks the imidazole-imidazole hydrogen bond and limits solubilization in DHPC detergent.

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言語: eng - English
 日付: 2023-06-072023-12
 出版の状態: 出版
 ページ: -
 出版情報: -
 目次: -
 査読: 査読あり
 識別子(DOI, ISBNなど): DOI: 10.1016/j.yjsbx.2023.100090
 学位: -

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Project information

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Project name : We acknowledge financial support from the Max Planck Society and the DFG Emmy Noether program (grant AN 1316/1-1)
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出版物 1

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出版物名: Journal of Structural Biology: X
  省略形 : JSBX
種別: 学術雑誌
 著者・編者:
所属:
出版社, 出版地: San Diego, CA : Elsevier
ページ: - 巻号: 8 通巻号: 100090 開始・終了ページ: - 識別子(ISBN, ISSN, DOIなど): ISSN: 2590-1524
CoNE: https://pure.mpg.de/cone/journals/resource/2590-1524