6BVF

Cryo-EM Structure of Hepatitis B virus T=4 capsid in complex with the fluorescent allosteric modulator HAP-TAMRA

Summary for 6BVF

• Entry DOI: 10.2210/pdb6bvf/pdb
• EMDB information: 7294 7295
• Descriptor: Capsid protein, Heteroaryldihydropyrimidine tetramethylrodamine (2 entities in total)
• Functional Keywords: capsid, cpam, antiviral, fluorescent, 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: 69043.27

Authors

Schlicksup, C.,Wang, J.C.,Zlotnick, A. (deposition date: 2017-12-12, release date: 2018-02-07, Last modification date: 2024-05-15)

Primary citation

Schlicksup, C.J.,Wang, J.C.,Francis, S.,Venkatakrishnan, B.,Turner, W.W.,VanNieuwenhze, M.,Zlotnick, A.
Hepatitis B virus core protein allosteric modulators can distort and disrupt intact capsids.
Elife, 7:-, 2018

PubMed Abstract: 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.

PubMed: 29377794
DOI: 10.7554/eLife.31473

Experimental method

ELECTRON MICROSCOPY (4 Å)