Takashi Kuzuhara, Daisuke Kise, Hiroko Yoshida, Ta. Structural basis of the influenza A virus RNA polymerase PB2 RNA-binding domain containing the pathogenicity-determinant lysine 627 residue. J. Biol. Chem, 10.1074/jbc.C800224200
Since the influenza A virus has an RNA genome, its RNA-dependent RNA polymerase, comprising the PA, PB1 and PB2 subunits, is essential for viral transcription and replication. The binding of RNA primers/promoters to the polymerases is an initiation step in viral transcription. In our current study, we reveal the 2.7 ? tertiary structure of the C-terminal RNA-binding domain of PB2 by X-ray crystallography. This domain incorporates lysine 627 of PB2, and this residue is associated with the high pathogenicity and host range restriction of influenza A virus. We found from our current analyses that this lysine is located in a unique "f"-shaped structure consisting of a helix and an encircled loop within the PB2 domain. By electrostatic analysis we identified a highly basic groove along with this f loop and found that lysine 627 is located in the f loop. A PB2 domain mutant in which glutamic acid is substituted at position 627 shows significantly lower RNA-binding activity. This is the first report to show a relationship between RNA-binding activity and the pathogenicity-determinant lysine 627. Using the Matras program for protein 3D structural comparisons, we further found that the helix bundles in the PB2 domain are similar to that of activator 1, the 40 kDa subunit of DNA replication clamp loader (replication factor C), which is also an RNA-binding protein. This suggests a functional and structural relationship between the RNA-binding mechanisms underlying both influenza A viral transcription and cellular DNA replication. Our present results thus provide important new information for developing novel drugs that target the primer/promoter RNA-binding of viral RNA polymerases.
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