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Letter

Nature 454, 1123-1126 (28 August 2008) | doi:10.1038/nature07120; Received 25 March 2008; Accepted 23 May 2008; Published online 9 July 2008

Open Innovation Challenges

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

Xiaojing He1, Jie Zhou1, Mark Bartlam2, Rongguang Zhang3, Jianyuan Ma1, Zhiyong Lou4, Xuemei Li1,4, Jingjing Li1, Andrzej Joachimiak3, Zonghao Zeng1, Ruowen Ge5, Zihe Rao1,2,4 & Yingfang Liu1

  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 Rao1,2,4Yingfang 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).

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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 binding3, 4; PA is implicated in RNA replication5, 6, 7, 8, 9, 10 and proteolytic activity11, 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 (PAC, residues 257–716) in complex with the PA-binding region of PB1 (PB1N, residues 1–25). PAC has a fold resembling a dragon's head with PB1N clamped into its open 'jaws'. PB1N is a known inhibitor that blocks assembly of the polymerase heterotrimer and abolishes viral replication. Our structure provides details for the binding of PB1N to PAC 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 PAC with the lambda3 reovirus polymerase structure, and docking the PAC structure into an available low resolution electron microscopy map.