tetano
Editor, Senior Moderator
PLoS One. 2015 Aug 12;10(8):e0135487. doi: 10.1371/journal.pone.0135487. eCollection 2015.
[h=1]The Mechanism by which 146-N-Glycan Affects the Active Site of Neuraminidase.[/h] Liu P[SUP]1[/SUP], Wang Z[SUP]1[/SUP], Zhang L[SUP]1[/SUP], Li D[SUP]1[/SUP], Lin J[SUP]1[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] One of the most conserved glycosylation sites of neuraminidase (NA) is 146-N-glycan. This site is adjacent to the 150-cavity of NA, which is found within the active site and thought to be a target for rational drug development against the antiviral resistance of influenza. Here, through a total of 2.4 μs molecular dynamics (MD) simulations, we demonstrated that 146-N-glycan can stabilize the conformation of the 150-loop that controls the volume of the 150-cavity. Moreover, with 146-N-glycan, our simulation result was more consistent with crystal structures of NAs than simulations conducted without glycans. Cluster analysis of the MD trajectories showed that 146-N-glycan adopted three distinct conformations: monomer-bridged, dimer-bridged and standing. Of these conformations, the dimer-bridged 146-N-glycan was the most stable one and contributed to stabilization of the 150-loop conformation. Furthermore, our simulation revealed that various standing conformations of 146-N-glycan could block the entrance of the binding pocket. This result was consistent with experimental data and explained the relatively low activity of inhibitors with flexible substituents toward the 150-cavity. Together, our results lead us to hypothesize that rigid and hydrophobic substituents could serve as better inhibitors targeting the 150-cavity.
PMID: 26267136 [PubMed - in process] Free full text
[h=1]The Mechanism by which 146-N-Glycan Affects the Active Site of Neuraminidase.[/h] Liu P[SUP]1[/SUP], Wang Z[SUP]1[/SUP], Zhang L[SUP]1[/SUP], Li D[SUP]1[/SUP], Lin J[SUP]1[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] One of the most conserved glycosylation sites of neuraminidase (NA) is 146-N-glycan. This site is adjacent to the 150-cavity of NA, which is found within the active site and thought to be a target for rational drug development against the antiviral resistance of influenza. Here, through a total of 2.4 μs molecular dynamics (MD) simulations, we demonstrated that 146-N-glycan can stabilize the conformation of the 150-loop that controls the volume of the 150-cavity. Moreover, with 146-N-glycan, our simulation result was more consistent with crystal structures of NAs than simulations conducted without glycans. Cluster analysis of the MD trajectories showed that 146-N-glycan adopted three distinct conformations: monomer-bridged, dimer-bridged and standing. Of these conformations, the dimer-bridged 146-N-glycan was the most stable one and contributed to stabilization of the 150-loop conformation. Furthermore, our simulation revealed that various standing conformations of 146-N-glycan could block the entrance of the binding pocket. This result was consistent with experimental data and explained the relatively low activity of inhibitors with flexible substituents toward the 150-cavity. Together, our results lead us to hypothesize that rigid and hydrophobic substituents could serve as better inhibitors targeting the 150-cavity.
PMID: 26267136 [PubMed - in process] Free full text