tetano
Editor, Senior Moderator
Sci Rep. 2017 Aug 24;7(1):9385. doi: 10.1038/s41598-017-09538-x.
[h=1]Structural basis for therapeutic inhibition of influenza A polymerase PB2 subunit.[/h] Ma X[SUP]1,[/SUP][SUP]2[/SUP], Xie L[SUP]3[/SUP], Wartchow C[SUP]4,[/SUP][SUP]5[/SUP], Warne R[SUP]6[/SUP], Xu Y[SUP]5[/SUP], Rivkin A[SUP]5[/SUP], Tully D[SUP]5[/SUP], Shia S[SUP]4[/SUP], Uehara K[SUP]3[/SUP], Baldwin DM[SUP]7[/SUP], Muiru G[SUP]7[/SUP], Zhong W[SUP]7[/SUP], Zaror I[SUP]3[/SUP], Bussiere DE[SUP]4,[/SUP][SUP]5[/SUP], Leonard VHJ[SUP]8[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Influenza virus uses a unique mechanism to initiate viral transcription named cap-snatching. The PB2 subunit of the viral heterotrimeric RNA polymerase binds the cap structure of cellular pre-mRNA to promote its cleavage by the PA subunit. The resulting 11-13 capped oligomer is used by the PB1 polymerase subunit to initiate transcription of viral proteins. VX-787 is an inhibitor of the influenza A virus pre-mRNA cap-binding protein PB2. This clinical stage compound was shown to bind the minimal cap-binding domain of PB2 to inhibit the cap-snatching machinery. However, the binding of this molecule in the context of an extended form of the PB2 subunit has remained elusive. Here we generated a collection of PB2 truncations to identify a PB2 protein representative of its structure in the viral heterotrimeric protein. We present the crystal structure of VX-787 bound to a PB2 construct that recapitulates VX-787's biological antiviral activity in vitro. This co-structure reveals more extensive interactions than previously identified and provides insight into the observed resistance profile, affinity, binding kinetics, and conformational rearrangements induced by VX-787.
PMID: 28839261 DOI: 10.1038/s41598-017-09538-x
[h=1]Structural basis for therapeutic inhibition of influenza A polymerase PB2 subunit.[/h] Ma X[SUP]1,[/SUP][SUP]2[/SUP], Xie L[SUP]3[/SUP], Wartchow C[SUP]4,[/SUP][SUP]5[/SUP], Warne R[SUP]6[/SUP], Xu Y[SUP]5[/SUP], Rivkin A[SUP]5[/SUP], Tully D[SUP]5[/SUP], Shia S[SUP]4[/SUP], Uehara K[SUP]3[/SUP], Baldwin DM[SUP]7[/SUP], Muiru G[SUP]7[/SUP], Zhong W[SUP]7[/SUP], Zaror I[SUP]3[/SUP], Bussiere DE[SUP]4,[/SUP][SUP]5[/SUP], Leonard VHJ[SUP]8[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Influenza virus uses a unique mechanism to initiate viral transcription named cap-snatching. The PB2 subunit of the viral heterotrimeric RNA polymerase binds the cap structure of cellular pre-mRNA to promote its cleavage by the PA subunit. The resulting 11-13 capped oligomer is used by the PB1 polymerase subunit to initiate transcription of viral proteins. VX-787 is an inhibitor of the influenza A virus pre-mRNA cap-binding protein PB2. This clinical stage compound was shown to bind the minimal cap-binding domain of PB2 to inhibit the cap-snatching machinery. However, the binding of this molecule in the context of an extended form of the PB2 subunit has remained elusive. Here we generated a collection of PB2 truncations to identify a PB2 protein representative of its structure in the viral heterotrimeric protein. We present the crystal structure of VX-787 bound to a PB2 construct that recapitulates VX-787's biological antiviral activity in vitro. This co-structure reveals more extensive interactions than previously identified and provides insight into the observed resistance profile, affinity, binding kinetics, and conformational rearrangements induced by VX-787.
PMID: 28839261 DOI: 10.1038/s41598-017-09538-x