Nucleoside Monophosphate Complex Structures of the Endonuclease Domain from the Influenza Virus Polymerase PA Subunit Reveal the Substrate Binding Site inside the Catalytic Center
-
- Cong Zhao
- Structural Biology Laboratory, Tsinghua University, Beijing 100084, China
-
- Zhiyong Lou
- Structural Biology Laboratory, Tsinghua University, Beijing 100084, China
-
- Yu Guo
- College of Life Sciences and Tianjin State Laboratory of Protein Science, Nankai University, Tianjin 300071, China
-
- Ming Ma
- National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China
-
- Yutao Chen
- National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China
-
- Shuaiyi Liang
- Structural Biology Laboratory, Tsinghua University, Beijing 100084, China
-
- Liang Zhang
- College of Life Sciences and Tianjin State Laboratory of Protein Science, Nankai University, Tianjin 300071, China
-
- Shoudeng Chen
- National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China
-
- Xuemei Li
- National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China
-
- Yingfang Liu
- National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China
-
- Mark Bartlam
- College of Life Sciences and Tianjin State Laboratory of Protein Science, Nankai University, Tianjin 300071, China
-
- Zihe Rao
- Structural Biology Laboratory, Tsinghua University, Beijing 100084, China
Description
<jats:title>ABSTRACT</jats:title> <jats:p> Highly pathogenic influenza virus strains currently in circulation pose a significant risk of a global pandemic. Following the reported crystal structure of the endonuclease domain from the avian influenza virus polymerase PA subunit, here we report the results of a systematic X-ray crystallographic analysis of its complex with adenosine, uridine, and thymidine nucleoside monophosphates (NMPs). Electron density corresponding to the monophosphate moiety of each nucleotide was apparent in each NMP complex and bound to the catalytic metal. A hydrophobic site was found to contribute to nucleoside binding. The NMP complex structures should represent the conformation of the bound product after nuclease cleavage. Moreover, one solvent molecule was found to occupy an equivalent position to the second reported Mn <jats:sup>2+</jats:sup> ion, where it mediates the interaction between bound NMPs and the N-terminal PA domain in the presence of the Mg <jats:sup>2+</jats:sup> ion. The results presented here indicate a possible cleavage mechanism and identify a distinct nucleotide binding pocket. The identification of this binding pocket opens a new avenue for anti-influenza drug discovery, targeting the cap-dependent endonuclease, in response to the worldwide threat of influenza. </jats:p>
Journal
-
- Journal of Virology
-
Journal of Virology 83 (18), 9024-9030, 2009-09-15
American Society for Microbiology
- Tweet
Details 詳細情報について
-
- CRID
- 1363388843566534272
-
- ISSN
- 10985514
- 0022538X
-
- Data Source
-
- Crossref