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

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Title: Real-time tracking of drug binding to influenza A M2 reveals a high energy barrier
Authors: Kumar Tekwani Movellan, Melanie Wegstroth, Kerstin Overkamp, Andrei Leonov, Stefan Becker, Loren B. Andreas
Source: Journal of Structural Biology: X, Vol 8, Iss , Pp 100090- (2023)
Publisher Information: Elsevier, 2023.
Publication Year: 2023
Collection: LCC:Biology (General)
Subject Terms: Magic-angle spinning, Proton channel, Drug binding, Solid-state NMR, Binding kinetics, Biology (General), QH301-705.5
More Details: 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.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 2590-1524
Relation: http://www.sciencedirect.com/science/article/pii/S2590152423000065; https://doaj.org/toc/2590-1524
DOI: 10.1016/j.yjsbx.2023.100090
Access URL: https://doaj.org/article/6126c5d4268f427484adf5d7d99bc435
Accession Number: edsdoj.6126c5d4268f427484adf5d7d99bc435
Database: Directory of Open Access Journals
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  Data: Journal of Structural Biology: X, Vol 8, Iss , Pp 100090- (2023)
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  Data: Elsevier, 2023.
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  Data: 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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