The mechanism by which influenza A virus nucleoprotein forms oligomers and binds RNA

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Abstract
The structure of the influenza A virus nucleoprotein has proved elusive. But now its crystal structure has been determined, to reveal a crescent-shaped molecule containing connected head and body regions with a groove in between to accommodate the viral RNA. Now the contact points between this protein and other parts of the virus particle can be visualized, which should help in the development of antiviral therapeutics for influenza. The structure of the influenza virus A nucleoprotein is visualized, revealing connected head and body regions with a groove in between for the viral RNA to sit. Influenza A viruses pose a serious threat to world public health, particularly the currently circulating avian H5N1 viruses. The influenza viral nucleoprotein forms the protein scaffold of the helical genomic ribonucleoprotein complexes, and has a critical role in viral RNA replication1. Here we report a 3.2 Å crystal structure of this nucleoprotein, the overall shape of which resembles a crescent with a head and a body domain, with a protein fold different compared with that of the rhabdovirus nucleoprotein2,3. Oligomerization of the influenza virus nucleoprotein is mediated by a flexible tail loop that is inserted inside a neighbouring molecule. This flexibility in the tail loop enables the nucleoprotein to form loose polymers as well as rigid helices, both of which are important for nucleoprotein functions. Single residue mutations in the tail loop result in the complete loss of nucleoprotein oligomerization. An RNA-binding groove, which is found between the head and body domains at the exterior of the nucleoprotein oligomer, is lined with highly conserved basic residues widely distributed in the primary sequence. The nucleoprotein structure shows that only one of two proposed nuclear localization signals are accessible, and suggests that the body domain of nucleoprotein contains the binding site for the viral polymerase. Our results identify the tail loop binding pocket as a potential target for antiviral development.