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TitleLocal Stabilization of Subunit-Subunit Contacts Causes Global Destabilization of Hepatitis B Virus Capsids.
Journal, issue, pagesACS Chem Biol, Vol. 15, Issue 6, Page 1708-1717, Year 2020
Publish dateJun 19, 2020
AuthorsChristopher John Schlicksup / Patrick Laughlin / Steven Dunkelbarger / Joseph Che-Yen Wang / Adam Zlotnick /
PubMed AbstractDevelopment 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 ...Development 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.
External linksACS Chem Biol / PubMed:32369333 / PubMed Central
MethodsEM (single particle)
Resolution3.7 - 4.6 Å
Structure data

EMDB-21653, PDB-6wfs:
Cryo-EM Structure of Hepatitis B virus T=4 capsid in complex with the antiviral molecule DBT1
Method: EM (single particle) / Resolution: 4.6 Å

EMDB-21654:
Focused asymmetric reconstruction of the hexameric icosahedral 2-fold region of a Heptatis B virus T=4 capsid in complex with the antiviral DBT1
Method: EM (single particle) / Resolution: 3.7 Å

EMDB-21655:
Focused asymmetric reconstruction of a pentamer of capsid protein subunits surrounding an icosahedral 5-fold axis from a Heptatis B virus capsid in complex with an antiviral molecule
Method: EM (single particle) / Resolution: 3.7 Å

Chemicals

ChemComp-U0A:
11-oxo-N-[2-(4-sulfamoylphenyl)ethyl]-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide

Source
  • hepatitis b virus genotype d subtype adw
KeywordsVIRUS LIKE PARTICLE / capsid / antiviral / HBV

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