6WFS

Cryo-EM Structure of Hepatitis B virus T=4 capsid in complex with the antiviral molecule DBT1

Summary for 6WFS

• Entry DOI: 10.2210/pdb6wfs/pdb
• EMDB information: 21653 21654 21655
• Descriptor: Capsid protein, 11-oxo-N-[2-(4-sulfamoylphenyl)ethyl]-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide (2 entities in total)
• Functional Keywords: capsid, antiviral, hbv, virus like particle
• Biological source: Hepatitis B virus genotype D subtype adw (isolate United Kingdom/adyw/1979)
• Total number of polymer chains: 4
• Total formula weight: 68978.55

Authors

Schlicksup, C.,Laughlin, P.,Dunkelbarger, S.,Wang, J.C.,Zlotnick, A. (deposition date: 2020-04-03, release date: 2020-06-03, Last modification date: 2024-03-06)

Primary citation

Schlicksup, C.J.,Laughlin, P.,Dunkelbarger, S.,Wang, J.C.,Zlotnick, A.
Local Stabilization of Subunit-Subunit Contacts Causes Global Destabilization of Hepatitis B Virus Capsids.
Acs Chem.Biol., 15:1708-1717, 2020

PubMed Abstract: 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.

PubMed: 32369333
DOI: 10.1021/acschembio.0c00320

Experimental method

ELECTRON MICROSCOPY (4.6 Å)