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Download fileLocal Stabilization of Subunit–Subunit Contacts Causes Global Destabilization of Hepatitis B Virus Capsids
journal contribution
posted on 2020-05-19, 18:12 authored by Christopher
John Schlicksup, Patrick Laughlin, Steven Dunkelbarger, Joseph Che-Yen Wang, Adam ZlotnickDevelopment
of antiviral molecules that bind virion is a strategy
that remains in its infancy, and the details of their mechanisms are
poorly understood. Here we investigate the behavior of DBT1, a dibenzothiazepine
that specifically interacts with the capsid protein of hepatitis B
virus (HBV). We found that DBT1 stabilizes protein–protein
interaction, accelerates capsid assembly, and can induce formation
of aberrant particles. Paradoxically, DBT1 can cause preformed capsids
to dissociate. These activities may lead to (i) assembly of empty
and defective capsids, inhibiting formation of new virus, and (ii)
disruption of mature viruses, which are metastable, to inhibit new
infection. Using cryo-electron microscopy, we observed that DBT1 led
to asymmetric capsids where well-defined DBT1 density was bound at
all intersubunit contacts. These results suggest that DBT1 can support
assembly by increasing buried surface area but induce disassembly
of metastable capsids by favoring asymmetry to induce structural defects.