ArticleProtein science : a publication of the Protein Society2022
Predicted structure of the hepatitis B virus polymerase reveals an ancient conserved protein fold.
Article in Protein science : a publication of the Protein Society, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 22 citations in OpenAlex.
- Hepatitis B virus ribonuclease H inhibitors: Coming of age?Antiviral research · 2026Review
- Hepatitis B Virus Nucleocapsid Assembly.Journal of molecular biology · 2025Review
- Discovery ofInternational journal of molecular sciences · 2025Article
- Meeting report: 38th international conference on antiviral research in Las Vegas, United States of America, March 17-21, 2025.Antiviral research · 2025Article
- Efficacy andAntimicrobial agents and chemotherapy · 2025Article
- Deviated binding of anti-HBV nucleoside analog E-CFCP-TP to the reverse transcriptase active site attenuates the effect of drug-resistant mutations.Scientific reports · 2024Article
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- Small Molecule Drugs Targeting Viral Polymerases.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Significance of hepatitis B virus capsid dephosphorylation via polymerase.Journal of biomedical science · 2024Article
- Identification and assessment of the 1,6-dihydroxy-pyridin-2-one moiety as privileged scaffold for HBV ribonuclease H inhibition.Antiviral research · 2024Article
- In vitro evaluation of tropolone absorption, metabolism, and clearance.Antiviral research · 2023Article
- Targeting Ribonucleases with Small Molecules and Bifunctional Molecules.ACS chemical biology · 2023Review
- Hepatitis B Virus Epsilon (ε) RNA Element: Dynamic Regulator of Viral Replication and Attractive Therapeutic Target.Viruses · 2023Review
- Virtual Screening of Hepatitis B Virus Pre-Genomic RNA as a Novel Therapeutic Target.Molecules (Basel, Switzerland) · 2023Article
- Predicted structure of the hepatitis B virus polymerase reveals an ancient conserved protein fold.Protein science : a publication of the Protein Society · 2022Article
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Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Hepatitis B virus (HBV) chronically infects >250 million people. It replicates by a unique protein-primed reverse transcription mechanism, and the primary anti-HBV drugs are nucleos(t)ide analogs targeting the viral polymerase (P). P has four domains compared to only two in most reverse transcriptases: the terminal protein (TP) that primes DNA synthesis, a spacer, the reverse transcriptase (RT), and the ribonuclease H (RNase H). Despite being a major drug target and catalyzing a reverse transcription pathway very different from the retroviruses, HBV P has resisted structural analysis for decades. Here, we exploited computational advances to model P. The TP wrapped around the RT domain rather than forming the anticipated globular domain, with the priming tyrosine poised over the RT active site. The orientation of the RT and RNase H domains resembled that of the retroviral enzymes despite the lack of sequences analogous to the retroviral linker region. The model was validated by mapping residues with known surface exposures, docking nucleic acids, mechanistically interpreting mutations with strong phenotypes, and docking inhibitors into the RT and RNase H active sites. The HBV P fold, including the orientation of the TP domain, was conserved among hepadnaviruses infecting rodent to fish hosts and a nackednavirus, but not in other non-retroviral RTs. Therefore, this protein fold has persisted since the hepadnaviruses diverged from nackednaviruses >400 million years ago. This model will advance mechanistic analyses into the poorly understood enzymology of HBV reverse transcription and will enable drug development against non-active site targets for the first time.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.