Hepatitis B virus core protein allosteric modulators can distort and disrupt intact capsids

Christopher John Schlicksup, Joseph Che Yen Wang, Samson Francis, Balasubramanian Venkatakrishnan, William W. Turner, Michael Vannieuwenhze, Adam Zlotnick

Research output: Contribution to journalArticlepeer-review

68 Scopus citations


Defining mechanisms of direct-acting antivirals facilitates drug development and our understanding of virus function. Heteroaryldihydropyrimidines (HAPs) inappropriately activate assembly of hepatitis B virus (HBV) core protein (Cp), suppressing formation of virions. We examined a fluorophore-labeled HAP, HAP-TAMRA. HAP-TAMRA induced Cp assembly and also bound pre-assembled capsids. Kinetic and spectroscopic studies imply that HAP-binding sites are usually not available but are bound cooperatively. Using cryo-EM, we observed that HAP-TAMRA asymmetrically deformed capsids, creating a heterogeneous array of sharp angles, flat regions, and outright breaks. To achieve high resolution reconstruction (<4 Å), we introduced a disulfide crosslink that rescued particle symmetry. We deduced that HAP-TAMRA caused quasi-sixfold vertices to become flatter and fivefold more angular. This transition led to asymmetric faceting. That a disordered crosslink could rescue symmetry implies that capsids have tensegrity properties. Capsid distortion and disruption is a new mechanism by which molecules like the HAPs can block HBV infection.

Original languageEnglish (US)
Article numbere31473
StatePublished - Jan 29 2018

All Science Journal Classification (ASJC) codes

  • General Neuroscience
  • General Immunology and Microbiology
  • General Biochemistry, Genetics and Molecular Biology


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