tetano
Editor, Senior Moderator
J Gen Virol. 2016 May 6. doi: 10.1099/jgv.0.000500. [Epub ahead of print]
[h=1]A molecular modeling approach to understand the effect of co-evolutionary mutations (V344M, I354L) identified in the PB2 subunit of influenza A 2009 pandemic H1N1 virus on m7GTP ligand binding.[/h] Bhoye D[SUP]1[/SUP], Behera AK[SUP]2[/SUP], Cherian SS[SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] The cap binding domain of the polymerase basic 2 (PB2) subunit of influenza polymerases plays a critical role in mediating the "cap-snatching" mechanism by binding the 5' cap of host pre-mRNAs during viral mRNA transcription. Monitoring variations in the PB2 protein is thus vital for evaluating the pathogenic potential of the virus. Based on selection pressure analysis of PB2 gene sequences of the pandemic H1N1 (pH1N1) viruses of the period 2009-2014, we identified a site 344V/M in the vicinity of the cap binding pocket showing evidence of adaptive evolution and another co-evolving residue 354I/L in close vicinity. Modeling the 3D-structure of the pH1N1 PB2 cap binding domain, docking of the pre-mRNA cap analog, m7GTP, and molecular dynamics (MD) simulation studies of the docked complexes performed for four observed PB2 variants, showed that the complex possessing V344M with I354L, possessed better ligand binding affinity due to additional hydrogen bond contacts between m7GTP and key residues His432 and Arg355 that was attributed to a displacement of the 424 loop and a flip of the side chain of Arg355 respectively.The identified co-evolutionary mutations (V344M, I354L) were found to be established in the PB2 gene of the pH1N1 viral population over the period 2010-2014. The study demonstrates the molecular basis for the enhanced m7GTP ligand binding affinity with the 344M-354L synergistic combination in PB2. Furthermore, the insight gained into understanding the molecular mechanism of cap binding in pH1N1 viruses may be useful for designing novel drugs targeting the PB2 cap binding domain.
PMID: 27154164 [PubMed - as supplied by publisher]
[h=1]A molecular modeling approach to understand the effect of co-evolutionary mutations (V344M, I354L) identified in the PB2 subunit of influenza A 2009 pandemic H1N1 virus on m7GTP ligand binding.[/h] Bhoye D[SUP]1[/SUP], Behera AK[SUP]2[/SUP], Cherian SS[SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] The cap binding domain of the polymerase basic 2 (PB2) subunit of influenza polymerases plays a critical role in mediating the "cap-snatching" mechanism by binding the 5' cap of host pre-mRNAs during viral mRNA transcription. Monitoring variations in the PB2 protein is thus vital for evaluating the pathogenic potential of the virus. Based on selection pressure analysis of PB2 gene sequences of the pandemic H1N1 (pH1N1) viruses of the period 2009-2014, we identified a site 344V/M in the vicinity of the cap binding pocket showing evidence of adaptive evolution and another co-evolving residue 354I/L in close vicinity. Modeling the 3D-structure of the pH1N1 PB2 cap binding domain, docking of the pre-mRNA cap analog, m7GTP, and molecular dynamics (MD) simulation studies of the docked complexes performed for four observed PB2 variants, showed that the complex possessing V344M with I354L, possessed better ligand binding affinity due to additional hydrogen bond contacts between m7GTP and key residues His432 and Arg355 that was attributed to a displacement of the 424 loop and a flip of the side chain of Arg355 respectively.The identified co-evolutionary mutations (V344M, I354L) were found to be established in the PB2 gene of the pH1N1 viral population over the period 2010-2014. The study demonstrates the molecular basis for the enhanced m7GTP ligand binding affinity with the 344M-354L synergistic combination in PB2. Furthermore, the insight gained into understanding the molecular mechanism of cap binding in pH1N1 viruses may be useful for designing novel drugs targeting the PB2 cap binding domain.
PMID: 27154164 [PubMed - as supplied by publisher]