1. National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
2. College of Life Sciences and Tianjin State Laboratory of Protein Sciences, Nankai University, Tianjin 300071, China
3. Midwest Center for Structural Genomics and Structural Biology Center, Biosciences Division, Argonne National Laboratory, Argonne, Illinois 60439, USA
4. Laboratory of Structural Biology, Tsinghua University, Beijing 100084, China
5. Department of Biological Sciences, National University of Singapore, 117543 Singapore

Correspondence to: Zihe Rao^1,2,4Yingfang Liu¹ Correspondence and requests for materials should be addressed to Z.R. (Email: raozh@xtal.tsinghua.edu.cn) or Y.L. (Email: liuy@ibp.ac.cn).

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 3 reovirus polymerase structure, and docking the PA_C structure into an available low resolution electron microscopy map.

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