A Crystal Structure of the Dengue Virus NS5 Protein Reveals a Novel Inter-domain Interface Essential for Protein Flexibility and Virus Replication

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DENV causes widespread mosquito-borne viral infections worldwide and nearly 40% of the world’s population is at risk of being infected. Currently, no licensed vaccines or specific drugs are available to treat severe infections by DENV. NS5 is a large protein of 900 amino acids composed of two domains with several key enzymatic activities for viral RNA replication in the host cell and constitutes a prime target for the design of antiviral inhibitors. We succeeded in trapping a stable conformation of the full-length NS5 protein and report its crystal structure at a resolution of 2.3 Å. This conformation reveals the entire inter-domain region and clarifies the determinants of NS5 flexibility. The inter-domain interface is stabilized by several polar contacts between residues projecting from the MTase and RdRp domains of NS5. Several evolutionarily conserved residues at the interface play a crucial role for virus replication as shown by reverse genetics, although the analogous mutations mostly do not abolish the in vitro enzymatic activities of the recombinant proteins.

Vyšlo v časopise: A Crystal Structure of the Dengue Virus NS5 Protein Reveals a Novel Inter-domain Interface Essential for Protein Flexibility and Virus Replication. PLoS Pathog 11(3): e32767. doi:10.1371/journal.ppat.1004682
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004682

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