Nucleoside Monophosphate Complex Structures of the Endonuclease Domain from the Influenza Virus Polymerase PA Subunit Reveal the Substrate Binding Site inside the Catalytic Center
| Autor: | Zhiyong Lou, Liang Zhang, Yu Guo, Ming Ma, Cong Zhao, Zihe Rao, Yutao Chen, Shuaiyi Liang, Shoudeng Chen, Yingfang Liu, Mark Bartlam, Xuemei Li |
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| Rok vydání: | 2009 |
| Předmět: |
Immunology
Orthomyxoviridae Crystallography X-Ray Microbiology Viral Proteins Endonuclease Catalytic Domain Virology Magnesium Nucleotide Binding site Polymerase Nucleoside binding chemistry.chemical_classification Manganese Nuclease Binding Sites Influenza A Virus H5N1 Subtype biology Nucleotides Structure and Assembly Endonucleases RNA-Dependent RNA Polymerase biology.organism_classification chemistry Biochemistry Insect Science Solvents biology.protein Nucleoside |
| Zdroj: | Journal of Virology. 83:9024-9030 |
| ISSN: | 1098-5514 0022-538X |
| Popis: | 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 2+ ion, where it mediates the interaction between bound NMPs and the N-terminal PA domain in the presence of the Mg 2+ 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. |
| Databáze: | OpenAIRE |
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