TY - JOUR
T1 - Local Stabilization of Subunit-Subunit Contacts Causes Global Destabilization of Hepatitis B Virus Capsids
AU - Schlicksup, Christopher John
AU - Laughlin, Patrick
AU - Dunkelbarger, Steven
AU - Wang, Joseph Che Yen
AU - Zlotnick, Adam
N1 - Funding Information:
This effort was funded by NIH grant R01-AI144022 to A.Z. Some EM work was supported by a grant from the Indiana Clinical and Translational Sciences Institute (CTSI) to A.Z. We made use of the Indiana University Electron Microscopy Center, the Purdue University Cryo-EM center, and the IU Physical Biochemistry Instrumentation facility. A.Z. has an interest in biotech companies developing HBV-directed antiviral agents. S.D. is now an employee of Door Pharmaceuticals.
Publisher Copyright:
Copyright © 2020 American Chemical Society.
PY - 2020/6/19
Y1 - 2020/6/19
N2 - 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.
AB - 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.
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U2 - 10.1021/acschembio.0c00320
DO - 10.1021/acschembio.0c00320
M3 - Article
C2 - 32369333
AN - SCOPUS:85086748106
SN - 1554-8929
VL - 15
SP - 1708
EP - 1717
JO - ACS Chemical Biology
JF - ACS Chemical Biology
IS - 6
ER -