Journal article
Identification of hepatitis B virus core protein residues critical for capsid assembly, pgRNA encapsidation and resistance to capsid assembly modulators
Antiviral research, v 191, 105080
01 Jul 2021
PMID: 33933516
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Assembly of hepatitis B virus (HBV) capsids is driven by the hydrophobic interaction of core protein (Cp) at dimer-dimer interface. Binding of core protein allosteric modulators (CpAMs) to a hydrophobic “HAP” pocket formed between the inter-dimer interface strengths the dimer-dimer interaction and misdirects the assembly of Cp dimers into non-capsid Cp polymers or morphologically normal capsids devoid of viral pregenomic (pg) RNA and DNA polymerase. In this study, we performed a systematic mutagenesis analysis to identify Cp amino acid residues at Cp dimer-dimer interface that are critical for capsid assembly, pgRNA encapsidation and resistance to CpAMs. By analyzing 70 mutant Cp with a single amino acid substitution of 25 amino acid residues around the HAP pocket, our study revealed that residue W102 and Y132 are critical for capsid assembly. However, substitution of many other residues did not significantly alter the amount of capsids, but reduced the amount of encapsidated pgRNA, suggesting their critical roles in pgRNA packaging. Interestingly, several mutant Cp with a single amino acid substitution of residue P25, T33 or I105 supported high levels of DNA replication, but conferred strong resistance to multiple chemotypes of CpAMs. In addition, we also found that WT Cp, but not the assembly incompetent Cp, such as Y132A Cp, interacted with HBV DNA polymerase (Pol). This later finding implies that encapsidation of viral DNA polymerase may depend on the interaction of Pol with a capsid assembly intermediate, but not free Cp dimers. Taking together, our findings reported herein shed new light on the mechanism of HBV nucleocapsid assembly and mode of CpAM action.
•Cp dimer-dimer interface interaction differentially modulates the assembly of empty capsids and nucleocapsids.•Cp residues W102 and Y132 play critical role in capsid assembly.•Mutations at P25, T33 and I105 confer resistance to multiple chemotypes of CpAMs.•HBV DNA polymerase interacts with wild-type, but not the assembly incompetent Cp.
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Details
- Title
- Identification of hepatitis B virus core protein residues critical for capsid assembly, pgRNA encapsidation and resistance to capsid assembly modulators
- Creators
- Yue Luo - Second Xiangya Hospital of Central South UniversityJunjun Cheng - Baruch S. Blumberg InstituteZhanying Hu - Baruch S. Blumberg InstituteHaiqun Ban - Baruch S. Blumberg InstituteShuo Wu - Institute of Medicinal Plant DevelopmentNicky Hwang - Baruch S. Blumberg InstituteJohn Kulp - Baruch S. Blumberg InstituteYuhuan Li - CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, ChinaYanming Du - Baruch S. Blumberg InstituteJinhong Chang - Baruch S. Blumberg InstituteUsha Viswanathan - Baruch S. Blumberg InstituteJu-Tao Guo - Baruch S. Blumberg Institute
- Publication Details
- Antiviral research, v 191, 105080
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000663041800002
- Scopus ID
- 2-s2.0-85105260938
- Other Identifier
- 991020547610504721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Pharmacology & Pharmacy
- Virology