Journal
JOURNAL OF VIROLOGY
Volume 83, Issue 18, Pages 9024-9030Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.00911-09
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Funding
- National Natural Science Foundation of China [30870486, 3059943]
- National Major Project of China [2009zx/0004, 2009zx09311-001]
- Ministry of Science and Technology ( MOST) [2006CB806503, 2006CB10901, 2007CB914300]
- MOST [2006DFB32420]
- 863 Project [2006AA020502, 2006AA02A322]
- KNAW [2008AA000238]
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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 Mn2+ ion, where it mediates the interaction between bound NMPs and the N-terminal PA domain in the presence of the Mg2+ 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.
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