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Scientific result | Structural biology | Simulation ＆ modelling | Artificial intelligence
Researchers from the team "Interactions and assembly mechanisms of Proteins and Peptides" (I2BC) unveil an atomic model of the hepatitis E virus replication polyprotein obtained with the AlphaFold artificial intelligence program. The model provides a better understanding of how this RNA virus multiplies its genome in infected cells.
Hepatitis E is an inflammation of the liver caused by infection with the hepatitis E virus (HEV). There are an estimated 20 million HEV infections worldwide each year and 3.3 million symptomatic cases of hepatitis E. The disease is usually self-limiting. However, it can sometimes progress to acute liver failure, which is an increased risk in pregnant women. Moreover, it evolves into a chronic infection in the majority of immunocompromised persons. There is currently no specific treatment. Ribavirin, an antiviral drug, can be prescribed to immunocompromised persons but not to pregnant women because of its teratogenic effects. A better characterization of the life cycle of the virus is needed to develop specific vaccines or antivirals.
The artificial intelligence-based program AlphaFold (developed by DeepMind) has already demonstrated its ability to produce relevant structural models of proteins, even in the absence of strong sequence identity with proteins of known structure. Using the program, the I2BC's Protein and Peptide Interactions and Assembly Mechanisms team modeled the three-dimensional structure of the 1700-residue polyprotein pORF1, which contains the enzymatic activities necessary for the synthesis of new HEV genomes in infected cells.
In a paper published in Virology, the authors describe the resulting structure of pORF1. It is a protein with five domains. The first of these contains both the activities necessary to cap the new viral RNAs and membrane-interacting elements. Until now, these two activities were attributed to two separate domains (methyltransferase domain and Y domain). The authors propose that this domain assembles into a dodecamer, forming a pore that couples the acquisition of the cap by newly synthesized RNAs to their translocation from the replication membrane compartment to the cytosol.
This work constitutes a step forward in the definition of molecular targets of future HEV antivirals.
To go further, read the news published on I2BC website:
« Accurate atomic model of the hepatitis E virus replication polyprotein ».
Sonia Fieulaine, Thibault Tubiana, Stéphane Bressanelli. De novo modelling of HEV replication polyprotein: Five-domain breakdown and involvement of flexibility in functional regulation. | Virology, 578, January 2023, Pages 128-140, https://doi.org/10.1016/j.virol.2022.12.002
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