Giuseppe
Emeritus
J Virol. 2009 Jul 8. [Epub ahead of print]
Nucleoside Monophosphate Complex Structures of the Endonuclease Domain from the Influenza Polymerase PA Subunit Reveal the Substrate Binding Site inside the Catalytic Center.
Zhao C, Lou Z, Guo Y, Ma M, Chen Y, Liang S, Zhang L, Chen S, Li X, Liu Y, Bartlam M, Rao Z. Structural Biology Laboratory, Tsinghua University, Beijing, 100084, China; College of Life Sciences and Tianjin State Laboratory of Protein Science, Nankai University, Tianjin 300071, China; National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing, 100101, China.
Highly pathogenic influenza strains currently in circulation pose the 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 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 NMPs 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 PAN in the presence of 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 world-wide threat of influenza.
PMID: 19587036 [PubMed - as supplied by publisher]
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Nucleoside Monophosphate Complex Structures of the Endonuclease Domain from the Influenza Polymerase PA Subunit Reveal the Substrate Binding Site inside the Catalytic Center.
Zhao C, Lou Z, Guo Y, Ma M, Chen Y, Liang S, Zhang L, Chen S, Li X, Liu Y, Bartlam M, Rao Z. Structural Biology Laboratory, Tsinghua University, Beijing, 100084, China; College of Life Sciences and Tianjin State Laboratory of Protein Science, Nankai University, Tianjin 300071, China; National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing, 100101, China.
Highly pathogenic influenza strains currently in circulation pose the 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 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 NMPs 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 PAN in the presence of 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 world-wide threat of influenza.
PMID: 19587036 [PubMed - as supplied by publisher]
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