The structural basis for an essential subunit interaction in influenza virus RNA polymerase

Influenza virus: polymerase structures determined Influenza A virus polymerase consists of three proteins, PA, PB1 and PB2, and is critical for transcription and replication. Two groups now report the crystal structure of the avian H5N1 PA C-terminal domain in complex with the PA binding domain of PB1. The structure work may be useful for the design of novel antiviral drugs. Influenza A virus is a major human and animal pathogen with the potential to cause catastrophic loss of life. The virus reproduces rapidly, mutates frequently and occasionally crosses species barriers. The recent emergence in Asia of avian influenza related to highly pathogenic forms of the human virus has highlighted the urgent need for new effective treatments 1 . Here we demonstrate the importance to viral replication of a subunit interface in the viral RNA polymerase, thereby providing a new set of potential drug binding sites entirely independent of surface antigen type. No current medication targets this heterotrimeric polymerase complex. All three subunits, PB1, PB2 and PA, are required for both transcription and replication 2 , 3 , 4 . PB1 carries the polymerase active site, PB2 includes the capped-RNA recognition domain, and PA is involved in assembly of the functional complex 5 , 6 , 7 , but so far very little structural information has been reported for any of them 8 , 9 , 10 , 11 . We describe the crystal structure of a large fragment of one subunit (PA) of influenza A RNA polymerase bound to a fragment of another subunit (PB1). The carboxy-terminal domain of PA forms a novel fold, and forms a deep, highly hydrophobic groove into which the amino-terminal residues of PB1 can fit by forming a 3 10 helix.