Molecular elucidation of drug-induced abnormal assemblies of the hepatitis B virus capsid protein by solid-state NMR

Lauriane Lecoq, Louis Brigandat, Rebecca Huber, Marie-Laure Fogeron, Shishan Wang, Marie Dujardin, Mathilde Briday, Thomas Wiegand, Morgane Callon, Alexander Malär, David Durantel, Dara Burdette, Jan Martin Berke, Beat H. Meier (), Michael Nassal () and Anja Böckmann ()
Additional contact information
Lauriane Lecoq: UMR 5086 CNRS/Université de Lyon
Louis Brigandat: UMR 5086 CNRS/Université de Lyon
Rebecca Huber: UMR 5086 CNRS/Université de Lyon
Marie-Laure Fogeron: UMR 5086 CNRS/Université de Lyon
Shishan Wang: UMR 5086 CNRS/Université de Lyon
Marie Dujardin: UMR 5086 CNRS/Université de Lyon
Mathilde Briday: UMR 5086 CNRS/Université de Lyon
Thomas Wiegand: ETH Zurich
Morgane Callon: ETH Zurich
Alexander Malär: ETH Zurich
David Durantel: UMR 5286, Centre Léon Bérard
Dara Burdette: Gilead Sciences
Jan Martin Berke: Janssen Pharmaceutica N.V
Beat H. Meier: ETH Zurich
Michael Nassal: University of Freiburg
Anja Böckmann: UMR 5086 CNRS/Université de Lyon

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Hepatitis B virus (HBV) capsid assembly modulators (CAMs) represent a recent class of anti-HBV antivirals. CAMs disturb proper nucleocapsid assembly, by inducing formation of either aberrant assemblies (CAM-A) or of apparently normal but genome-less empty capsids (CAM-E). Classical structural approaches have revealed the CAM binding sites on the capsid protein (Cp), but conformational information on the CAM-induced off-path aberrant assemblies is lacking. Here we show that solid-state NMR can provide such information, including for wild-type full-length Cp183, and we find that in these assemblies, the asymmetric unit comprises a single Cp molecule rather than the four quasi-equivalent conformers typical for the icosahedral T = 4 symmetry of the normal HBV capsids. Furthermore, while in contrast to truncated Cp149, full-length Cp183 assemblies appear, on the mesoscopic level, unaffected by CAM-A, NMR reveals that on the molecular level, Cp183 assemblies are equally aberrant. Finally, we use a eukaryotic cell-free system to reveal how CAMs modulate capsid-RNA interactions and capsid phosphorylation. Our results establish a structural view on assembly modulation of the HBV capsid, and they provide a rationale for recently observed differences between in-cell versus in vitro capsid assembly modulation.

Date: 2023
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DOI: 10.1038/s41467-023-36219-3

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