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Dimer Organization of Membrane‐Associated NS5A of Hepatitis C Virus as Determined by Highly Sensitive 1 H‐Detected Solid‐State NMR
Author(s) -
Jirasko Vlastimil,
Lends Alons,
Lakomek NilsAlexander,
Fogeron MarieLaure,
Weber Marco E.,
Malär Alexander A.,
Penzel Susanne,
Bartenschlager Ralf,
Meier Beat H.,
Böckmann Anja
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202013296
Subject(s) - ns5a , linker , dimer , chemistry , membrane , crystallography , membrane protein , biophysics , combinatorial chemistry , hepatitis c virus , biochemistry , virus , biology , virology , hepacivirus , organic chemistry , computer science , operating system
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 self‐interaction not reflected in previous crystal structures. In conclusion, we provide the first characterization of NS5A AH‐linker‐D1 in a lipidic environment shedding light onto the mode‐of‐action of clinically used NS5A inhibitors.