ArticleProceedings of the National Academy of Sciences of the United States of America2013
Thermodynamic origins of protein folding, allostery, and capsid formation in the human hepatitis B virus core protein.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 72 citations in OpenAlex.
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- Discovery of novel small molecules targeting hepatitis B virus core protein from marine natural products with HiBiT-based high-throughput screening.Acta pharmaceutica Sinica. B · 2024Article
- Conformationally Constrained Isoquinolinones as Orally Efficacious Hepatitis B Capsid Assembly Modulators.ACS medicinal chemistry letters · 2024Article
- The Complex Role of HBeAg and Its Precursors in the Pathway to Hepatocellular Carcinoma.Viruses · 2023Review
- Design, synthesis, and biological evaluation of novel sulfamoylbenzamide derivatives as HBV capsid assembly modulators.Bioorganic chemistry · 2022Article
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- Structural and Functional Characterizations of Cancer Targeting Nanoparticles Based on Hepatitis B Virus Capsid.International journal of molecular sciences · 2021Article
- Hepatitis B Core Protein Capsids.Sub-cellular biochemistry · 2021Review
- Targeting the multifunctional HBV core protein as a potential cure for chronic hepatitis B.Antiviral research · 2020Review
- Dynamics of Hepatitis B Virus Capsid Protein Dimer Regulate Assembly through an Allosteric Network.ACS chemical biology · 2020Article
- Ensembles of Hydrophobicity Scales as Potent Classifiers for Chimeric Virus-Like Particle Solubility - An Amino Acid Sequence-Based Machine Learning Approach.Frontiers in bioengineering and biotechnology · 2020Article
- Structural Differences between the Woodchuck Hepatitis Virus Core Protein in the Dimer and Capsid States Are Consistent with Entropic and Conformational Regulation of Assembly.Journal of virology · 2019Article
- Process monitoring of virus-like particle reassembly by diafiltration with UV/Vis spectroscopy and light scattering.Biotechnology and bioengineering · 2019Article
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Authors and funding
6 authors at 4 institutions in 2 countries.
Funding
Abstract
HBc, the capsid-forming "core protein" of human hepatitis B virus (HBV), is a multidomain, α-helical homodimer that aggressively forms human HBV capsids. Structural plasticity has been proposed to be important to the myriad functions HBc mediates during viral replication. Here, we report detailed thermodynamic analyses of the folding of the dimeric HBc protomer under conditions that prevented capsid formation. Central to our success was the use of ion mobility spectrometry-mass spectrometry and microscale thermophoresis, which allowed folding mechanisms to be characterized using just micrograms of protein. HBc folds in a three-state transition with a stable, dimeric, α-helical intermediate. Extensive protein engineering showed thermodynamic linkage between different structural domains. Unusual effects associated with mutating some residues suggest structural strain, arising from frustrated contacts, is present in the native dimer. We found evidence of structural gatekeepers that, when mutated, alleviated native strain and prevented (or significantly attenuated) capsid formation by tuning the population of alternative native conformations. This strain is likely an evolved feature that helps HBc access the different structures associated with its diverse essential functions. The subtle balance between native and strained contacts may provide the means to tune conformational properties of HBc by molecular interactions or mutations, thereby conferring allosteric regulation of structure and function. The ability to trap HBc conformers thermodynamically by mutation, and thereby ablate HBV capsid formation, provides proof of principle for designing antivirals that elicit similar effects.
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