Crystal structure of the polymerase PAC–PB1N complex from an avian influenza H5N1 virus

Abstract

The recent emergence of highly pathogenic avian influenza A virus strains with subtype H5N1 pose a global threat to human health¹. Elucidation of the underlying mechanisms of viral replication is critical for development of anti-influenza virus drugs². The influenza RNA-dependent RNA polymerase (RdRp) heterotrimer has crucial roles in viral RNA replication and transcription. It contains three proteins: PA, PB1 and PB2. PB1 harbours polymerase and endonuclease activities and PB2 is responsible for cap binding^3,4; PA is implicated in RNA replication^5,6,7,8,9,10 and proteolytic activity^11,12,13,14, although its function is less clearly defined. Here we report the 2.9 ångström structure of avian H5N1 influenza A virus PA (PA_C, residues 257–716) in complex with the PA-binding region of PB1 (PB1_N, residues 1–25). PA_C has a fold resembling a dragon’s head with PB1_N clamped into its open ‘jaws’. PB1_N is a known inhibitor that blocks assembly of the polymerase heterotrimer and abolishes viral replication. Our structure provides details for the binding of PB1_N to PA_C at the atomic level, demonstrating a potential target for novel anti-influenza therapeutics. We also discuss a potential nucleotide binding site and the roles of some known residues involved in polymerase activity. Furthermore, to explore the role of PA in viral replication and transcription, we propose a model for the influenza RdRp heterotrimer by comparing PA_C with the λ3 reovirus polymerase structure, and docking the PA_C structure into an available low resolution electron microscopy map.