Dimer Organization of Membrane-Associated NS5A of Hepatitis C Virus as Determined by Highly Sensitive 1 H-Detected Solid-State NMR - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Angewandte Chemie International Edition Année : 2021

Dimer Organization of Membrane-Associated NS5A of Hepatitis C Virus as Determined by Highly Sensitive 1 H-Detected Solid-State NMR

Résumé

The Hepatitis C virus nonstructural protein 5A (NS5A) is a membrane-associated protein involved in multiple steps of the viral life cycle. Direct-acting antivirals (DAAs) targeting NS5A are a cornerstone of antiviral therapy, but the mode-of-action of these drugs is poorly understood. This is due to the lack of information on the membrane-bound NS5A structure. Herein, we present the structural model of an NS5A AH-linker-D1 protein reconstituted as proteoliposomes. We use highly sensitive proton-detected solid-state NMR methods suitable to study samples generated through synthetic biology approaches. Spectra analyses disclose that both the AH membrane anchor and the linker are highly flexible. Paramagnetic relaxation enhancements (PRE) reveal that the dimer organization in lipids requires a new type of NS5A selfinteraction not reflected in previous crystal structures. In conclusion, we provide the first characterization of NS5A AHlinker-D1 in a lipidic environment shedding light onto the mode-of-action of clinically used NS5A inhibitors.
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Dates et versions

hal-03366997 , version 1 (06-10-2021)

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Vlastimil Jirasko, Alons Lends, Nils-Alexander Lakomek, Marie-Laure Fogeron, Marco E. Weber, et al.. Dimer Organization of Membrane-Associated NS5A of Hepatitis C Virus as Determined by Highly Sensitive 1 H-Detected Solid-State NMR. Angewandte Chemie International Edition, 2021, 60 (10), pp.5339-5347. ⟨10.1002/anie.202013296⟩. ⟨hal-03366997⟩
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