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Structural basis for therapeutic inhibition of influenza A polymerase PB2 subunit

Ma, Xiaolei, Xie, Lili, Wartchow, Charles, Warne, Robert, Rivkin, Alexey, Tully, David, Shia, Steven, Uehara, Kyoko, Muiru, Gladys, Zhong, Weidong, Zaror, Isabel, Bussiere, Dirksen, Leonard, Vincent and Baldwin, Dianna (2017) Structural basis for therapeutic inhibition of influenza A polymerase PB2 subunit. Scientific reports.


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.

Item Type: Article
Date Deposited: 02 Jan 2018 00:45
Last Modified: 02 Jan 2018 00:45


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