Nature 458, 909-913 (16 April 2009) | doi:10.1038/nature07720; Received 28 November 2008; Accepted 12 December 2008; Published online 4 February 2009

Crystal structure of an avian influenza polymerase PAN reveals an endonuclease active site

Puwei Yuan1,6, Mark Bartlam2,6, Zhiyong Lou3,6, Shoudeng Chen1, Jie Zhou1, Xiaojing He1, Zongyang Lv1, Ruowen Ge4, Xuemei Li1,3, Tao Deng2,5, Ervin Fodor5, Zihe Rao1,2,3 & Yingfang Liu1

  1. National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
  2. College of Life Sciences and Tianjin Key Laboratory of Protein Science, Nankai University, Tianjin 300071, China
  3. Laboratory of Structural Biology, Tsinghua University, Beijing 100084, China
  4. Department of Biological Sciences, National University of Singapore, Singapore 117543
  5. Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
  6. These authors contributed equally to this work.

Correspondence to: Zihe Rao1,2,3Yingfang Liu1 Correspondence and requests for materials should be addressed to Z.R. (Email: raozh@xtal.tsinghua.edu.cn) and Y.L. (Email: liuy@ibp.ac.cn).

The heterotrimeric influenza virus polymerase, containing the PA, PB1 and PB2 proteins, catalyses viral RNA replication and transcription in the nucleus of infected cells. PB1 holds the polymerase active site1 and reportedly harbours endonuclease activity2, whereas PB2 is responsible for cap binding2, 3, 4. The PA amino terminus is understood to be the major functional part of the PA protein and has been implicated in several roles, including endonuclease5 and protease activities6 as well as viral RNA/complementary RNA promoter binding7. Here we report the 2.2 ångström (Å) crystal structure of the N-terminal 197 residues of PA, termed PAN, from an avian influenza H5N1 virus. The PAN structure has an alpha/beta architecture and reveals a bound magnesium ion coordinated by a motif similar to the (P)DXN(D/E)XK motif characteristic of many endonucleases. Structural comparisons and mutagenesis analysis of the motif identified in PAN provide further evidence that PAN holds an endonuclease active site. Furthermore, functional analysis with in vivo ribonucleoprotein reconstitution and direct in vitro endonuclease assays strongly suggest that PAN holds the endonuclease active site and has critical roles in endonuclease activity of the influenza virus polymerase, rather than PB1. The high conservation of this endonuclease active site among influenza strains indicates that PAN is an important target for the design of new anti-influenza therapeutics.


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